Competitive AMPA receptor antagonists

Competitive AMPA ReceptorAntagonists Daniela Catarzi, Vittoria Colotta, Flavia Varano Dipartimento di Scienze Farmaceutiche, Universita’ degli Studi di Firenze, Polo Scientifico, Via U. Schiff, 6-50019 Sesto Fiorentino (Firenze), Italy Published online 4 August 2006 in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/med.20084 !

Abstract: Glutamic acid (Glu) is the major excitatory neurotransmitter in the mammalian central nervous system (CNS) where it is involved in the physiological regulation of different processes. It has been well established that excessive endogenous Glu is associated with many acute and chronic neurodegenerative disorders such as cerebral ischaemia, epilepsy, amiotrophic lateral sclerosis, Parkinson’s, and Alzheimer’s disease. These data have consequently added great impetus to the research in this field. In fact, many Glu receptor antagonists acting at the N-methyl-D-aspartic acid (NMDA), 2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl)propionic acid (AMPA), and/or kainic acid (KA) receptors have been developed as research tools and potential therapeutic agents. Ligands showing competitive antagonistic action at the AMPA type of Glu receptors were first reported in 1988, and the systemically active 2,3-dihydroxy-6-nitro-7-sulphamoyl-benzo[f]quinoxaline (NBQX) was first shown to have useful therapeutic effects in animal models of neurological disease in 1990. Since then, the quinoxaline template has represented the backbone of various competitive AMPA receptor antagonists belonging to different classes which had been developed in order to increase potency, selectivity and water solubility, but also to prolong the ‘‘in vivo’’ action. Compounds that present better pharmacokinetic properties and less serious adverse effects with respect to the others previously developed are undergoing clinical evaluation. In the near future, the most important clinical application for the AMPA receptor antagonists will probably be as neuroprotectant in neurodegenerative diseases, such as epilepsy, for the treatment of patients not responding to current therapies. The present review reports the history of competitive AMPA receptor antagonists from 1988 up to today, providing a systematic coverage of both the open and patent literature. ß 2006 Wiley Periodicals, Inc. Med Res Rev, 27, No. 2, 239–278, 2007 Key words: glutamate receptor; AMPA receptor antagonists; neuroprotection

1. HISTORICAL PERSPECTIVES Glutamate (Glu) (1, Fig. 1) is the primary excitatory neurotransmitter in the mammalian central nervous system (CNS) and it plays a pivotal role in regulating neuronal activity. In particular, it is Correspondence to: Daniela Catarzi,Dipartimentodi Scienze Farmaceutiche,Universita’degli Studi di Firenze,Polo Scientifico,Via U. Schiff, 6-50019 Sesto Fiorentino (Firenze), Italy. E-mail: [email protected] Medicinal Research Reviews, Vol. 27, No. 2, 239 ^278, 2007 ß 2006 Wiley Periodicals, Inc.

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Figure 1. Ionotropic glutamate receptor agonists.

involved in mediating basal excitatory synaptic transmission and many forms of synaptic plasticity, such as long-term potentiation (LTP) and long-term depression (LTD), which are thought to be necessary for learning and memory.1,2 Discovery of the excitatory properties of Glu3–5 gave life to a new research field which has spanned more than 50 years. In the 1950s, Glu was proposed as a central synaptic transmitter due to its capability of causing convulsions.3,4 In the meantime, some studies demonstrated that Glu depolarized and excited central neurons,5 as it was expected for an excitatory neurotransmitter. Despite this evidence, for a long time it was thought that the effects exerted by Glu were nonspecific because it seemed to excite every kind of neuron tested. Many other aspects seemed to argue strongly against a transmitter role of Glu, which was not accepted for other 20 years. A very concise, but informative overview of the research developments in this field is reported in Reference [6]. Only within the past 10 years Glu has been widely accepted as a transmitter. In fact, as a result of biological and electrophysiological studies, understanding of the ion channel involvement in synaptic transmission has advanced enormously. Initial investigations demonstrated that Glu depolarized membranes, primarily as a result of an increase in membrane conductance to Naþ.7–9 However, the initial progress on Glu receptor research was significantly aided by advances in pharmacological studies. Indeed, the observations that Glu analogues such as N-methyl-D-aspartate (NMDA) (2, Fig. 1), quisqualate (QUIS) (3), and kainate (KA) (4) possessed different degrees of potency in diverse subclasses of neurons10 and that some Glu receptor antagonists (i.e., kynurenic acid, glutamate diethyl ester, and Mg2þ) produced differential effects on agonist responses,11–15 increased the knowledge of both glutamate receptor (GluRs) subtypes and their role in the CNS. Further progress in this research field was made by experimental studies showing that synaptic transmission in the CNS, both in vitro and in vivo, was reduced by these antagonists. In the beginning, GluRs were classified into NMDA, QUIS, and KA receptors according to their preferential exogenous agonist.12,13,16 Subsequently, it was demonstrated that the 2-amino-3-(3hydroxy-5-methylisoxazol-4-yl)propionic acid (AMPA) (5, Fig. 1) was a more selective quisqualatelike agonist than QUIS.17 This observation led to a new classification of the already known GluRs into NMDA, AMPA (instead of QUIS), and KA receptors.18 The NMDA receptor requires simultaneous binding of Glu to its specific site, and of the coagonist glycine to the Gly/NMDA receptor.19 Activation of these receptors, which directly gate ion channels, leads to the entry of cations (Naþ, Kþ, and/or Ca2þ) into the neurons eliciting their depolarization: for this reason, they are currently classified as ionotropic (ion channel forming) glutamate receptors (iGluRs).

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About 20 years ago, QUIS was shown to activate also phospholipase-coupled GluRs:20,21 the identification of this new class of receptors, later termed metabotropic (G-protein coupled) glutamate receptors (mGluRs), produced a new field of research22–24 which is still on the rise.25,26 Metabotropic GluRs modulate glutamatergic excitation by pre-synaptic, post-synaptic, and glial mechanism. To date, the heterogeneous mGluRs family consists of at least eight subtypes which have been cloned and termed mGluR1-8. These eight different receptors have been classified into three groups (groups I–III) on the basis of sequence similarity, pharmacology and transduction mechanism. Recently, the distinction between iGluRs and mGluRs has been questioned. In fact, some AMPA receptors appear to be physically coupled to GTP proteins, or to tyrosine kinase. However, the proteins that include the AMPA receptors do not contain the sequence of amino acids that is normally required for coupling mGluRs to G-proteins.27–29 In recent years, extensive research has been directed toward the clarification of GluR functions in the CNS.6,30 The physiological and pathological roles of NMDA19,31–34 and AMPA19,35–40 receptors have been well understood. On the contrary, the physiological function of the KA receptor family, comprising the low-affinity binding site and the high-affinity one, is still an open question.19,31,36,37,40,41 However, at the moment, a number of KA subunit-selective ligands have been identified which, together with selective AMPA receptor agonists and antagonists, are currently aiding progress in the understanding of KA receptor physiology and pathology.40,42,43 There is considerable evidence that AMPA receptors are involved in many neurological processes in the healthy as well in the diseased CNS.19,34–36,38,39 In addition, even if conventional wisdom has it that iGluRs are expressed almost exclusively in the CNS, the growing number of exceptions is forcing a revision of this point of view. For example, pancreatic islet cells express different iGluRs belonging to the AMPA and KA receptor subtypes.37,44 This observation raises the possibility that AMPA/KA receptors might be involved in disorders such as diabetes. However, it has been well established that overstimulation of AMPA receptors is one of the major causes of Ca2þ overload in cells, potentially leading to cell damage and death. These processes are strictly related to a large number of acute and chronic neurodegenerative pathologies such as cerebral ischaemia, epilepsy, amiotrophic lateral sclerosis, and Parkinson’s disease. Thus, AMPA receptor subtypes represent potential targets for therapeutic intervention in many neurological diseases. In particular, extensive work was addressed toward the development of selective antagonists, which proved to be particularly useful in the prevention and treatment of different neurological pathologies [for review articles see References 45–55]. The present review deals with those drugs that act as competitive antagonists on the AMPA receptor complex, but also on the KA receptor subtype. In fact, most of the competitive AMPA receptor antagonists reported till now have shown mixed AMPA/KA inhibitory activity, due to the fact that structural similarities and differences between these two diverse receptors are still unknown. For this reason, there are some difficulties in pharmacologically differentiating AMPA from KA receptors and vice versa. It has to be noted that AMPA receptor activity can be inhibited also by at least two other groups of substances by interacting with two other different binding sites on the AMPA receptor complex. These classes of substances are noncompetitive antagonists which bind to the polyamine site within the ion channel,47,51,54 and a group of negative allosteric modulators45–51,54,55 which interact with an allosteric-binding site distinct from that which binds positive allosteric modulators.45,46,49,50

2. AMPA RECEPTORS AND THEIR STRUCTURE The AMPA receptor, together with KA one, belongs to the subfamily of the non-NMDA receptors. For many years, AMPA and KA receptors have been considered as only one functional unit because of the historical difficulties in differentiating them. For this reason, they have been termed as

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AMPA/KA receptors. Classification of these receptors according to their preferred agonist has rapidly been superseded by a classification based on the proteins which form the receptor. The first Glu receptor subunit was cloned by the expression cloning approach using Xenopus oocytes and it is represented by the AMPA receptor subunit named GluR1.56 Subsequent cloning has led to three additional AMPA receptor subunits, GluR2-4,57,58 and five KA receptor subunits termed GluR5-7 and KA1-234,48,49 (Fig. 2). Application of molecular biological screening techniques led to the identification of 17 genes encoding proteins which, based on sequence comparison, belong to the iGluR superfamily.60 In addition to AMPA and KA receptor subunits, molecular cloning identified other subunits termed NR1, NR2A-D, and NR3A-B34,59 for the NMDA receptor complex (Fig. 2). All iGluRs (i.e., NMDA, AMPA, and KA receptors) are homo- or hetero-tetrameric proteins which are assembled to form a functional receptor-channel complex.59,61,62 Every receptor-channel is composed of four to five subunits62 which in general coassemble within families63 to produce many

Figure 2. Classification of glutamate receptors.

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receptor combinations: this variability can affect both the extent and kinetic of the channel’s electrophysiological response, thus justifying the enormous molecular and functional diversities among the iGluR families, diversities which are likely to be physiologically important.60 Mixed receptors of AMPA and KA subunits do not occur naturally.64,65 A mixed NMDA/AMPA receptor was described as a minor receptor in an amphibian, and may also be present in mammals.66 Eukaryotic iGluR subunits are each composed of an extracellular amino-terminal domain (ATD), a ligand binding domain (LBD), a transmembrane domain (TMD), and an intracellular carboxy-terminal domain (CTD) (Fig. 3).64,67 The channel-forming TMD contains three membranespanning segments (M1, M3, and M4) and the M2 ‘‘re-entrant loop.’’ Two extracellular segments, S1 and S2,68 have been shown to constitute the LBD which is responsible for the binding of both the neurotransmitter and the competitive agonists/antagonists. Glu binding to the extracellular LBD (S1S2) segment of the protein triggers a series of conformational changes that leads to receptor activation (formation of a cation-Ca2þ, Naþ, Kþ-selective transmembrane channel) and subsequent desensitization.69–71 The AMPA receptor subunits, GluR1-4, have a structure similar to that of all the other iGluR subunits, and exist in two, different, alternatively spliced isoforms, flip and flop, which show differences in their desensitization properties72 and their sensitivity to blockers of desensitization

Figure 3. General structure features and membrane topology of glutamate receptor subunits.

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such as cyclothiazide.73 In addition, the GluR2 subunit has shown to be particularly important for the functional properties of heteromeric AMPA receptors. In fact, many channel properties can be different, such as rectification and ion-selectivity of GluR2-containing heteromeric channel.61 AMPA receptors lacking this subunit show high-Ca2þ permeability, whereas heteromeric AMPA receptors containing GluR2 show low-Ca2þ permeability.74,75 A crucial amino acid residue in the channel pore region can be either arginine or glutamine: residue of the former is found in the GluR2, whereas the other three subunits contain the latter in the corresponding position (Q/R site) and this affects the channel electrophysiological properties.61 Determination of the structure of the S1S2 segment for the GluR2 subunit of the AMPA receptor, complemented by spectroscopic investigations76–80 and the vast existing electrophysiological data on the native receptor,70,81 has provided the first direct structural insight into how changes at the ligand binding site lead to a sequence of conformational modifications that regulate ion flow in the receptor channel. It is now universally accepted that the isolated LBD (S1S2) can be considered a representative model of the full functional GluR.76,82 In fact, the X-ray crystal structure of the GluR2 binding domain construct consisting of the extracellular segments S1 and S2 linked by a small polypeptide linker have greatly advanced characterization of the agonist binding domain of iGluRs (GluR2S1S2J).71,83 The binding of agonists to this construct yields a pharmacological profile comparable to that observed for the full-length receptor.76,82 A number of structures of GluR2-S1S2J in complex with different agonists83–89 as well as with competitive AMPA receptor antagonists (DNQX, Fig. 5) (6,7-dinitro-quinoxalin-2,3-dione) are now available.83,90 Thus, the solved crystal structure of GluR2 subunit with different competitive agonists and antagonists has opened the door to exploration of the mechanism of activation and desensitization of iGluRs70,71,83,91 and elucidated some details of ligand recognition thus certainly directing the future design of AMPA receptor ligands towards more rational approaches. In fact, an unresolved problem regards the difficulties in pharmacologically differentiating AMPA from KA receptors. Knowledge of the structure receptor proteins and receptor recognition site may pave the way for the rational design of selective compounds. Moreover, great interest has been directed toward the development of subunit selective compounds, whose discovery could open the possibility for characterization of the many subunits.

3. DISTRIBUTION OF THE AMPA RECEPTORS Using a variety of techniques (radioligand binding of [3H]AMPA,92 single-cell RT-PCR,93–95 in situ hybridization histochemistry57,60,96 and immunocytochemistry97), AMPA receptors have been shown to have a widespread distribution in the CNS. They have been found throughout the brain, with particularly high levels of expression in cerebral cortex, basal ganglia, thalamus and hypothalamus, hippocampus, cerebellum, and spinal cord.98,99 There are clear differences in the expression pattern of specific subunits as well as significant overlap, suggesting that a large number of subunit combinations can be expressed by individual neurons. One goal has been to determine the subunit composition of naturally occurring AMPA receptor complexes and relate their composition to their function. Many studies have reported the distribution of the AMPA receptor subunits in human brain but a description of their distribution and localization is beyond the scope of this review; however, other authors have exhaustively reviewed this research topic.60,100,101 Briefly, the development of selective subunit antibodies has enabled detailed localization studies for each subunit and revealed that GluR1 and GluR2, for example, have widely overlapping expression. Distribution profiles are important particularly for GluR2, since this subunit renders the channel impermeable for Ca2þ and influences receptor properties.74,75 GluR4 was suggested to be associated with fast AMPA responses.

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A growing body of evidence is confirming the presence of the AMPA receptors also in peripheral sites such as pancreas,37,44,102 heart,103 postganglionic sympathetic neurons104,105 cutaneous axons106 and enteric ganglia.107,108 Even though evidence derived from different studies is consistent with preferentially postsynaptic localization of AMPA receptors,109 recent observations have shown that they can also be found in the presynapse,110–112 on glutamatergic and other nerve terminals.110 In the mid 1990s, the role of AMPA receptors in modulating presynaptic dynamics was still unknown, but recently a very convincing case for inhibition of neurotransmitter release has been provided regarding GABAergic113 and glutamatergic terminals.114

4. PATHOPHYSIOLOGICAL ROLE OF AMPA RECEPTORS AND POTENTIAL THERAPEUTIC APPLICATIONS OF COMPETITIVE AMPA RECEPTOR ANTAGONISTS It is well known that overstimulation of iGluRs causes, at least in part, neurodegeneration. In fact, Glu can act as a neurotoxin, especially when energy supply is compromised.115 Thus, iGluR antagonists are considered to have clinical potential in many neurological disorders which range from acute (such as stroke, trauma, and epilepsy) to chronic neurodegenerative diseases (such as Parkinson’s disease and amiotrophic lateral sclerosis (ALS)). A great number of review articles have appeared on this topic,19,32–34,36,46,48,49,52,55 thus this section will provide only the most important information on AMPA receptor antagonists. It was reported that an increased synaptic release of Glu is present during periods of global and focal ischaemia116,117 and further studies provided evidence of the involvement of iGluR overstimulation in these neurological conditions.118–120 In many studies, AMPA receptor antagonists were demonstrated to be effective in reducing neuronal loss after focal ischaemia induced by middle cerebral artery (MCA) occlusion.121,122 The development of AMPA receptor antagonists as neuroprotective agents is a rational consequence of this evidence. Another field of potential therapeutic application of AMPA receptor antagonists is in epileptic conditions.48,49,52,55 In fact, activation of AMPA receptors is involved in both seizure initiation and maintenance.123–125 In particular, overactivation of AMPA receptors produced cell death by either necrotic or apoptotic mechanism.126 AMPA antagonists seemed to be able to reduce cell death as shown by numerous pharmacological studies.127,128 Competitive AMPA antagonists can be considered anticonvulsant agents with clinical potential, and even some currently used anticonvulsant drugs have antagonist action at AMPA receptors.129 The most common epileptic condition in humans is represented by temporal lobe epilepsy which can be compared to the neurological symptoms obtained in amygdala kindling animal model.130 In this model some competitive AMPA receptor antagonists have shown to be effective in blocking seizure initiation and propagation. An increased release of extracellular Glu was demonstrated after physical brain trauma,131,132 and injury was reduced by competitive AMPA receptor antagonists administered before insult or later.121 However, it has been reported that mixed AMPA/KA receptor antagonists are more effective in this model than AMPA receptor-selective drugs.133 The iGluRs which are present in the spinal cord play a pivotal role in pain transmission and seem to be involved in neuronal plasticity which accompanies sensitization to pain.134,135 Inhibition of spinal iGluRs has antinociceptive effect in many animal models. In fact, administration of competitive AMPA receptor antagonists has antinociceptive activity in rodents.136,137 However, the role of AMPA receptors in spinal pain transmission is not yet well characterized due to a lack of truly selective AMPA receptor antagonists. Competitive AMPA receptor antagonists have been shown to produce anxiolytic effects,138 but some contrasting data exist which cannot be easily explained.139

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An increased Glu release has been demonstrated also in hypoglycemic coma were neurodegeneration can be a possible outcome.116 Thus, AMPA receptor antagonists can be considered as potential therapeutic drugs in this acute condition. As a matter of a fact, the most important clinical application for competitive AMPA receptor antagonists in the near future seems to be as neuroprotectant in acute neurodegenerative diseases, yet interest in this field has grown enormously because of AMPA receptor involvement in nonneurological disorders.140 In particular, competitive AMPA receptor antagonists have been demonstrated to decrease mobility and invasive growth in tumor cells and enhance in vitro activity of cytostatic drugs, thus suggesting their synergistic anticancer potential.141–143 Furthermore, some recent studies have evaluated the behavioral effects of competitive AMPA receptor antagonists in animal models of substance abuse.144 The results obtained indicated that AMPA receptor antagonists are not able to prevent tolerance or dependence from developing, but they might ameliorate both the physical and emotional consequences of withdrawal, thus suggesting their potential therapeutic use for drug abuse. The research field on iGluR antagonists is in a state of explosive development,142,143,145 – 155 in particular for compounds acting at the AMPA receptor subtype whose activation is thought to be involved in a steadily increasing number of chronic and acute disorders. The current success of AMPA receptor antagonists (over other well pharmacologically characterized iGluR antagonists) is in part due to their greater clinical potential with respect, for example, to NMDA antagonists since they do not produce the adverse psychotomimetic and cardiovascular effects observed for the NMDA antagonists. However, it was demonstrated that AMPA and NMDA receptor antagonists can act synergistically in some epilepsy models;156 – 158 this additive effect could justify the high-anticonvulsant activity of some nonselective AMPA and NMDA receptor antagonists.159,160 However, despite their considerable clinical potential, the use of AMPA receptor antagonists in humans should be contemplated with high caution due to their widespread actions in the CNS. It has to be noted that only few clinical trials have been reported till now;161–166 in fact, the low-water solubility of most currently available AMPA receptor antagonists limit their entry as drug candidates. Fortunately, as reported below, recent breakthroughs in the development of water-soluble quinoxalinedione derivatives have been made. Preliminary studies in humans did not evidence any serious adverse effect at therapeutic doses with the exception of lack of motor coordination. However, the principal problem of most of the AMPA antagonists reported till now is the short duration of action and the absence of any oral activity, both properties being essential for treatment of chronic diseases. It is likely that these agents will be limited to the treatment of acute disorders, such as stroke and trauma.

5. DESIGN OF COMPETITIVE AMPA RECEPTOR ANTAGONISTS Currently, the design of new AMPA receptor ligands can be achieved by mapping of the AMPA receptor recognition site by computational methods, in combination with X-ray crystallographic analysis of cocrystallized complexes between ligands and the receptor-binding domain. The essential concern in designing AMPA receptor antagonists is not only their potency, but also their subunit selectivity. Although the role of different AMPA subunits has not yet been investigated, it is likely that differences among subtype combinations confer them with specific physiological properties and functions. Exploration of subunit-selective antagonists is becoming a general trend and a hot research field. In general, compounds that are selective for a subunit (or a combination of subunits) have great potential to overcome the disadvantages deriving from the widespread distribution of Glu activity sites.

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The increasing interest in developing subunit-selective ligands is emphasized by the evidence that modifications in subunit compositions can be observed as a consequence of precise diseases.167–173 Due to their few possible adverse effects, subunit-specific (or subunit-combination specific) AMPA antagonists could be more appropriate for prevention and treatment of chronic neurodegenerative diseases, whereas broad-spectrum AMPA receptor antagonists may be used for the treatment of acute neurological diseases. A. AMPA Analogues and Other Amino Acid Derivatives The introduction of [3H]AMPA as a radioligand174,175 paved the way for the pharmacological characterization of AMPA receptors and for the development of new AMPA receptor ligands. Different series of AMPA receptor antagonists are reported in the literature including AMPA-derived antagonists, developed taking AMPA as lead compound, and amino acid derivatives, designed using as templates other natural or synthetic amino acids endowed with agonist activity at the AMPA receptor. Analogues of AMPA having different substituents in the 5-position of the isoxazole nucleus were synthesized and used in SAR studies on AMPA receptor.176–182 Several synthetic amino acids such as AMPA receptor agonists and antagonists were reported by Krogsgaard–Larsen’s group which is at the forefront of this research field.183 Initial studies were directed toward the synthesis of AMPA analogues in which the methyl group in the 5-position of the isoxazole ring was replaced with different alkyl, aryl or heteroaryl groups. (R,S)-2-amino-3-(3-hydroxy-5-phenyl-4-isoxazolyl)propionate (APPA) (6, Fig. 4) was originally described as a weak partial agonist at the AMPA receptor.176 Subsequently, APPA was resolved into optically pure (R)- and (S)-APPA which were evaluated in electrophysiological assays:184 (S)-APPA was shown to be a full agonist whereas the (R)-form was devoid of excitatory activity, but it was demonstrated to competitively block the AMPA receptor. Thus, the observed partial agonist profile of (R,S)-APPA has to be ascribed to the combined effect of the full agonist (S)-APPA and the competitive antagonist (R)-APPA. This trend is common to a large group of AMPA-like compounds reported in the literature.178–181,183,185,186 AMPA was also converted into other AMPA receptor antagonists such as (R,S)-2-amino-3-(3carboxymethoxy-5-methyl-4-isoxazolyl)propionate (AMOA) (7, Fig. 4)187,188 and (R,S)-2-amino-3(3-carboxymethoxy-5-butyl-4-isoxazolyl)propionate (ATOA) (8, Fig. 4) where the oxygen at position 3 was substituted with an acetic side chain, or transformed into the corresponding 3-Omethylphosphonic acid derivative 9 (ATPO, Fig. 4) ((R,S)-2-amino-3-(3-phosphomethoxy-5-butyl4-isoxazolyl)propionate).189 AMOA proved to be a selective although rather weak AMPA receptor antagonist,188 but no neuroprotective effects toward AMPA-induced toxicity on cortical neurons were observed.187 The two tert-butyl derivatives ATOA and ATPO were competitive AMPA receptor antagonists and more potent and selective than AMOA. SAR studies on these derivatives showed that their potency was highly dependent on the nature of the distal acid moiety, the phosphonic acid generally being more effective than the corresponding acetic acid.189 ATOA was more recently showed to be also a partial agonist at recombinant GluR5 receptors.190 ATPO showed nonselective antagonist activity at GluR14 subunits and a weak partial agonist at GluR5 and GluR5/KA2 subunits.191 Later, the racemic ATPO was resolved into (S)- and (R)- ATPO. (R)-isomer was essentially inactive as an agonist or antagonist in all tests, whereas (S)-ATPO showed a profile similar to (R,S)-ATPO at GluR1-4 subunits, but was weakly active at the KA GluR5 subunit, and inactive at GluR6.192 Another series of AMPA receptor antagonists which showed significant receptor activity is that comprising the decahydroisoquinoline derivatives. Early studies found the (R,S)-6-tetrazolyl-ethyldecahydroisoquinoline-3-carboxylic acid derivative (LY-215490)193 to be a weak AMPA receptor antagonist: resolution gave the active stereoisomer (
)-(3S,4aR,6R,8aR) LY293558 (10, Fig. 4)194

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Figure 4. AMPA analogues and other amino acid derivatives.

which was shown to be neuroprotective in a cat focal ischaemia model.195 This derivative is very water soluble, thus allowing its infusion or parenteral injection as preferred route of administration. Thus, LY293558 was selected for clinical development as neuroprotective agent, but development was discontinued.164 The decahydroisoquinoline series has been widely investigated and it was demonstrated that AMPA receptor activity strictly depends on the stereochemistry as well as the distance of the polar side group (i.e., tetrazole in LY293558) at position 6 from the amino acid moiety on the decahydroisoquinoline scaffold. Compounds with trans ring-junction are inactive, suggesting the angular conformation as preferred with respect to the linear one. LY293558 has the optimal stereochemistry and spacer length (two carbon chain): C6 and C3 epimer are weakly active and inactive, respectively, at the AMPA receptor, while analogs with one-carbon spacer were NMDA selective. Other acidic bioisosteric groups besides the tetrazole nucleus were explored, including other five-membered heterocycles and carboxylic, phosphonic, sulfonic acids, and acyl sulphonamides.196–201 Subsequently, in vitro studies on LY293558 revealed that in addition to the potent antagonistic action at the AMPA receptor, similar binding activity was obtained at the KA GluR5 receptor subunit.201 Recently, LY293558 was tested in acute migraine and demonstrated to be effective in preclinical models.202 The racemic form LY215490 was developed as a potential agent in the treatment of cerebral infarction, cerebrovascular ischaemia, epilepsy, and as analgesic.164 Further studies on decahydroisoquinolines200,201 produced several compounds belonging to this series, showing in vivo efficacy, with (
)-LY377770 (11, Fig. 4) being a clinical candidate as neuroprotectant.

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Modification of the willardiine agonist ((S)-1-(2-amino-2-carboxy)ethyl-pirimidine-2,4-dione) yielded competitive AMPA receptor agonist and antagonists endowed with modest binding activity.203–207 Introduction of a carboxyalkyl chain in position 3 of the willardiine moiety shifted the activity from agonist to antagonist. AMPA versus KA receptor selectivity is influenced by the length of the alkyl spacer linking the carboxy group: an alkyl chain length equivalent to two methylene groups is optimal for antagonist activity and selectivity (vs. KA subtype) at the AMPA receptors. These studies produced UBP 277 (12, Fig. 4) and UBP 279 (13, Fig. 4) which showed to possess AMPA receptor antagonist activity.207 These compounds, as well as the amino acid derivatives previously discussed, have the advantage of being water soluble, thus allowing the preparation of aqueous solutions. Recent SAR analysis produced some information about the structural requirements for the design of novel willardiine analogues with AMPA receptor activity.207 Another interesting shift from agonist to antagonist activity was observed in a series of Nquinoxalin-2,3-dione-1-alanine derivatives and among them the 6,7-dimethyl-substituted compound (14, Fig. 4) was one of the most active, competitive AMPA receptor antagonists, within this series, although it is very weak. As in the case of the isoxazole nucleus in AMPA or other heterocycles, the quinoxalinedione moiety may function as an acidic bioisoster. The antagonism at the AMPA receptor seemed to be dependent on the presence of a steric bulk in the 6,7-position of the quinoxalinedione nucleus.208 B. Quinoxaline-2,3-Dione Derivatives The quinoxalinedione derivatives are one of the most important chemical classes of competitive AMPA receptor antagonists which are still undergoing intensive study. A great number of them have made it possible to test the importance of AMPA receptors in different disease models. However, early pharmacological studies have been hampered by the lack of potent and selective compounds. CNQX (14, Fig. 5) was, among the quinoxalinedione series, the first potent AMPA receptor antagonist to be discovered.209 Together with DNQX (15, Fig. 5) CNQX showed to be useful in developing and understanding of the pharmacology of this iGluR subtype.210 However, these compounds also have activity at the Gly/NMDA binding site, thus lacking sufficient selectivity to be really useful tools for the characterization of the AMPA receptors.211 Subsequently, NBQX (16, Fig. 5) was demonstrated to have improved AMPA receptor selectivity with respect to CNQX212 and thus, it was used as the antagonist of choice in many ‘‘in vitro’’ and ‘‘in vivo’’ models. SAR studies on the first generation of quinoxalinedione derivatives showed that electron withdrawing groups (EWG) on the bicyclic ring system, preferably NO2, greatly enhanced affinity at the AMPA receptors,213 affinity that is further increased by introduction of a second EWG, such as CN or NO2 in CNQX and DNQX, respectively. The idea that the imidazol-1-yl moiety could act as a bioisostere of the cyano and nitro groups in the quinoxalinedione series was developed by Yamanouchi, leading to the potent and selective AMPA receptor antagonist YM90K (17, Fig. 5).214 The above mentioned quinoxalinedione derivatives were used as lead compounds for the design of novel AMPA receptor antagonists. The goal to be reached was twofold: the need to find out potent and selective AMPA receptor antagonists which where also characterized by good physicochemical properties. In fact, the first reported quinoxalinedione derivatives such as DNQX and NBQX were eliminated as drug candidates because of the absence of ‘‘in vivo’’ activity following systemic administration. Moreover, the clinical development of NBQX was prevented by its low-water solubility at physiological pH, which, combined with a fast renal excretion would have caused crystallization in the kidneys at therapeutic doses.215 On the contrary, YM90K showed to be systemically active,214 but it has a short ‘‘in vivo’’ duration of action.216 Despite these limitations, the pharmacological properties of these quinoxalinedione derivatives were widely investigated. In fact, the anticonvulsant profile of NBQX was thoroughly characterized,217–221 and both NBQX and

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Figure 5. Quinoxalin-2,3-dione derivatives of great interest.

YM90K were evaluated for their anti-Parkinsonian properties,222,223 but other researchers had, however, failed to replicate these studies.224 Most simple quinoxalinedione derivatives showed limited water solubility which restricted efforts to formulate acceptable parenteral solutions. With this problem to solve, new compounds such as PNQX (18, Fig. 5)225 and YM872 (Zonampanel) (19, Fig. 5)226,227 were prepared as possible AMPA receptor antagonist candidates. PNQX was designed in order to improve aqueous solubility by introducing an ionizable-fused pyperidine ring on the benzo moiety. Unfortunately, PNQX showed low water solubility at physiological pH. PNQX was demonstrated to be equipotent to NBQX at the AMPA receptors, but it also possessed a significant affinity for the Gly/NMDA site. This result as well as the higher anticonvulsant activity with respect to NBQX led to the hypothesis that a relatively balanced binding profile at AMPA and Gly/NMDA sites may be optimal in achieving significant neuroprotective activity.225 YM872 is a very water-soluble AMPA antagonist due to the presence of a hydrophilic acetic acid side chain. This structural modification of YM90K made it possible to overcome the solubility problem met with other quinoxalinediones, but it also produced a compound with an affinity and selectivity profile similar to those of NBQX and YM90K.227,228 Subsequently, the quinoxalinedione ZK200775 (Fanampanel) (20, Fig. 5), bearing an attached hydrophilic methyl phosphonate side chain, was designed.138,229,230 Its excellent water solubility was ascribed to the presence of both the N-1 substituent and the bulky morpholino group at position 7 of the quinoxaline ring system. In fact, compounds like ZK200775 have been derived from the attempt to improve water solubility without losing activity at the AMPA receptor. Both YM872 and ZK200775 showed to be active in ‘‘in vivo’’ models of acute and ischaemic stroke. For this reason, they entered clinical trials. Unfortunately, the trial with ZK200775 was

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stopped prematurely,231 but that with YM872 was completed.165,166 While no details regarding the anticonvulsant profile of YM872 were published, extensive studies on the neuroprotective action of this compound have been recently reported.232,233 Moreover, YM872 demonstrated itself to be a novel remedy for malignant primary glioblastoma and displayed efficacy in brain hemorrhage and its symptoms.143,234 Neuroprotection in brain ischaemia has also been recently demonstrated for the first-generation quinoxalinedione AMPA receptor antagonist CNQX, despite its unfavorable physicochemical properties.235 YM90K demonstrated neuroprotective effects against cerebral ischaemic/postischaemic damage attenuating the loss of N-acetylaspartate (NAA) whose level was used as an index of neuroprotective effect.236 It has recently been reported147,237,238 that NBQX showed efficacy in the treatment of demyelinating disorders alone and in combination with the tripeptide Gly-Pro-Gly. Further ameliorated pharmacokinetic properties were obtained by Novartis by introducing an aminoalkyl phosphonic acid side chain on the fused benzo moiety of the quinoxalinedione scaffold. This research led to the discovery of AMP397A (21, Fig. 5) as a potent competitive AMPA receptor antagonist endowed with high selectivity over KA receptors.239,240 AMP397A combines high affinity for the AMPA receptor with good ‘‘in vivo’’ potency and oral activity.240,241 These characteristics led to it being as a drug candidate in anticonvulsant therapy. In fact, AMP397A showed high water solubility which also influences the good pharmacokinetic profile and the long duration of action.52,240 All the above discussed compounds and their congeners have provided the basis for the development of an AMPA receptor pharmacophore model (Fig. 6) which was reported by various groups.45,225,242 These models emphasized some important structural requirements for quinoxalinedione activity as AMPA receptor antagonists: (i) a NH proton donor that binds to a proton acceptor site of the receptor; (ii) the 2,3-dione moiety, which serves as potent hydrogen bond acceptor, able to engage a strong columbic interaction with a positive site of the receptor; (iii) a strong EWG, such as NO2, CN, CF3, halogen, at R7, which can act with twofold mechanism: by increasing the acidity of the NH at position 1 as well as providing a weak hydrogen bond interaction with a suitable receptor site. However, significant structural similarities exist between the AMPA receptor and the Gly/ NMDA site. In fact, several quinoxalin-2,3-dione derivatives showed mixed Gly/NMDA and AMPA receptor antagonist activity. A putative Gly/NMDA receptor pharmacophore model was reported, where regions of steric intolerance were identified.225,243,244 The first difference, but not truly discriminant between the two receptor sites, can be observed when EWG larger than a chlorine atom are introduced at R6 and R7 on the fused benzo moiety. In fact, in the Gly/NMDA receptor site, a size-limited binding cleft exists

Figure 6. Pharmacophore model of the AMPA receptor.

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which is just big enough to hardly accommodate a NO2 group, but it better tolerates a chlorine atom. One of the most discriminant differences between the two pharmacophore models can be identified when a bulky group, such as the 6-(imidazol-1-yl) moiety of YM90K (17, Fig. 5), is present at R6. Steric and electronic limitations for the binding at Gly/NMDA site exists also at the level of R5 and R6 substituents, as exemplified by the structure of selective AMPA receptor antagonists NBQX and PNQX. The difference45,225,242 –244 between the structural requirements for the binding at AMPA and Gly/NMDA sites facilitated the design of either selective or mixed AMPA and Gly/NMDA receptor antagonists. In fact, great effort was directed toward the development of new AMPA receptor antagonists which could have been useful for developing and understanding the pharmacology of the AMPA receptor subtype. The quinoxalinedione derivatives discussed above are representative of the most interesting compounds reported in the literature as AMPA receptor antagonists. Obviously, the number of compounds which were studied in order to identify these drug candidates was enormous. The great number of compounds reported in the patent literature and, to a minor extent, in the open literature, is the clear evidence of the intensive research carried out in this field. However, since most of the different quinoxalinedione derivatives have generally been described in patent literature, little biological and pharmacological data are reported. However, it seems interesting to provide a broad description of the extensive studies which have been fundamental for reaching the current progress report. The differently substituted quinoxalinediones will be discussed separately on the basis of the principal substituent position on the bicyclic ring system. This classification, though perfunctory, is guided by the evidence that introduction of suitable substituents on precise position(s) of the quinoxalinedione scaffold influences the potency and selectivity versus different iGluRs as well as pharmacokinetic properties, independently of other concurrent modifications. The classification and nomenclature are in line with those reported in other review articles.46,50 In this classification, the numbering of the quinoxalinedione nucleus reported in Figure 6 was followed, which, though uncorrected for the N-substituted quinoxalinedione compounds, facilitates the comprehension avoiding apparent contradiction and confusion. 1. N-4 Substituted Quinoxalin-2,3-Diones Polar and hydrophilic groups at R4 such as hydroxy, carboxyalkyl, and phosphonoalkyl are, in general, responsible for increased water solubility and improved binding affinity for the AMPA receptor. Initial studies on N-4 acetic acid derivatives were reported on quinoxalinediones bearing simple substituents, such as chlorine atom(s) or methyl group(s) at R6 and/or R7 (compounds 22, Fig. 7).245 However, most of these derivatives showed AMPA binding activity in the micro-molar range and, in general, are characterized by high potency at the Gly/NMDA site. The best results in the field of AMPA receptor antagonists were obtained on quinoxalinediones bearing more hindered substituents at R6 (see YM872, Fig. 5)214,226,229,246–250 as required by the AMPA pharmacophore model.225,242 The positive effect exerted by polar groups at R4 probably results from their acting as a supplementary interaction point which reinforces the binding with the AMPA receptor.242 This data was supported by the decreased AMPA receptor activity when nonpolar groups, such as alkyl or alkoxy, are present at the same position. Introduction of a hydroxy group at the 4-position of YM90K (Fig. 5) gave compound 23 (Fig. 7) which was the most potent (Ki ¼ 21 nM) and selective AMPA receptor antagonist in this series, with a 100-fold selectivity for AMPA over Gly/NMDA receptor.247 YM872, the carboxymethyl derivative of YM90K (Fig. 5) showed a similar AMPA receptor binding affinity (Ki ¼ 95 nM), but it was much more soluble than the parent compound YM90K. The utility of the carboxyalkyl side chain as well as the phosphonoalkyl group at R4 was investigated by varying the substitution pattern on the fused benzo moiety.251–253

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Figure 7. N-4 substituted quinoxalin-2,3-dione derivatives.

Many quinoxaline-2,3-dione compounds lacking the nitro group at R7 were studied. The 6-trifluoromethyl derivative 24a (Fig. 7) was reported as a potent AMPA receptor antagonist useful for the treatment of neurodegenerative diseases associated with overstimulation of AMPA receptors.230,254 Subsequently, its corresponding N-methylphosphonic acid derivative ZK202000 (24b) was reported to protect rodent brain against ischaemic and traumatic injury.230 2. C5-Substituted Quinoxalin-2,3-Diones In the last few years, several compounds bearing at R5 different side chains with amine functionality have been reported (Fig. 8). This modification was particularly lucky for developing drug candidates as it remarkably improves the physicochemical properties of compounds. These ameliorated pharmacokinetic characteristics may be in part attributed to a loss of molecule planarity, compared to the planar structure of quinoxalinedione derivatives, such as NBQX. However, the C-5 substituted compounds were, in general, mixed AMPA-Gly/NMDA receptor antagonists. The combined antagonist profile of these derivatives became particularly interesting when synergistic effect of AMPA and Gly/NMDA receptor antagonists was demonstrated ‘‘in vivo.’’156–158 Initial studies on C5-substituted compounds were reported in patent applications239,255–258 and the disclosed quinoxalinedione derivatives showed different degrees of potency and selectivity. The most potent compounds were reported by Novartis239,240,259–261 and Warner-Lambert,253,256,257,262 but they were found to also have good Gly/NMDA receptor binding affinity. The principal difference between the series reported by the two different research groups seems to be the orientation of the amino acid side chain at R5. In fact, the CH3 group at R6 of the Warner-Lambert series (i.e., compounds 25c,d) forces the aminomethyl chain to the opposite side with respect to that assumed by the C-5 substituent of Novartis compounds 25a,b, for which this forced conformation is prevented

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Figure 8. C-5 substituted quinoxalin-2,3-dione derivatives.

probably because R6 is an hydrogen atom. Another element that seems to influence AMPA versus Gly/NMDA selectivity in these compounds is the N-methylation of the amino acid side chain which is forced in an out of plane orientation. In fact, compounds 25b (AMPA, IC50 ¼ 340 nM; Gly/NMDA, I% ¼ 22), and 25d (AMPA, IC50 ¼ 120 nM; Gly/NMDA, IC50 ¼ 470 nM) are much more AMPA selective than the N-unsubstituted compounds 25a (AMPA, IC50 ¼ 160 nM; Gly/NMDA, IC50 ¼ 760 nM) and 25c (AMPA, IC50 ¼ 500 nM; Gly/NMDA, IC50 ¼ 20 nM), respectively. Further studies, directed toward compounds bearing an alkyl aminophosphonic acid side chain at R5, led Novartis to the identification of a series of potent and selective AMPA receptor antagonists240,241,263 for which the activity and selectivity was strictly dependent on different structural features: (i) the substitution pattern on the amine nitrogen, (ii) the chirality of the aminophosphonic acid side chain, and (iii) the nature of the substituent at R7. In fact, high selectivity toward the AMPA receptor was achieved when an ethyl group was present on the amino nitrogen together with a nitro group at R7 (compound 26, Fig. 8) (AMPA, IC50 ¼ 0.31 nM, Gly/NMDA I% (1mM) ¼ 25). These studies confirmed that N-alkylation of the R5 side chain nitrogen atom

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significantly modified the molecule conformation, thus enhancing the selectivity toward the AMPA receptor subtypes. These derivatives revealed to be particularly interesting due to their improved physicochemical properties, especially with regard to water solubility that positively influenced their duration of action. The importance of the orientation of the aminoalkyl substituent at R5 in the AMPA receptor ligand interaction was investigated even further by Warner-Lambert researchers.264–266 While the 5-methylsulfonamidomethyl derivative 27 showed to be active in the MES test,265 but none AMPA versus Gly/NMDA selectivity was observed, the 5-(2-oxo-1,3,4-oxadiazol-2-yl) derivative 28 demonstrated high potency as AMPA receptor antagonist.266 3. C-6 Substituted Quinoxalin-2,3-Dione Derivatives Most of these derivatives are quinoxalinediones bearing an EWG at R7 and an optional substituent at R4. As stated above, SAR studies indicated that the imidazol-1-yl moiety could function as a bioisostere of the cyano and nitro groups of CNQX and DNQX, respectively, and the resulting compound YM90K (Fig. 5) proved to be a potent and selective AMPA receptor antagonist.214 Others groups at R6 were introduced on the fused benzo ring and, among them, the 4-oxo-dihydropyridin-1yl, thus yielding derivative 29 (Fig. 9). This compound, though bearing a bulky substituent at R6, showed a mixed AMPA-Gly/NMDA receptor activity.267 The best results were obtained when suitable substituents were introduced at R6 with the contemporary presence at R4 of a polar side chain, such as an acetic group. Replacing the imidazol-1-yl group of YM872 (19, Fig. 5) with a pyrrole moiety provided a wide series of potent, selective and water soluble AMPA receptor antagonists.248– 250,268 LU112313 (30, Fig. 9) belongs to this series of 6-substituted quinoxalines showing a 400-fold selectivity for the AMPA receptor over the Gly/NMDA receptor site.133,248,250 This compound was demonstrated to be highly potent in the MES test and against AMPA-induced convulsions in mice.52 Whereas compounds 31a (Ki ¼ 70 nM), 31b (Ki ¼ 180 nM), and 32a (Ki ¼ 71 nM) are equipotent to YM872 (Ki ¼ 95 nM), derivatives 32b-e, bearing both a trifluoromethyl group at R7 and a phenylurea-substituted pyrrole moiety at R6, showed AMPA binding activity in the low micro-molar range (4 < Ki < 15 mM) and no affinity for the Gly/NMDA receptor up to 30 mM.248–250 These results, together with those obtained by the Warner-Lambert researchers, indicated that the trifluoromethyl group at R7 on the quinoxalinedione scaffold successfully replaced the nitro group, making the trifluoromethyl derivatives as possible drug candidates for long-term therapy. The Turski group contribution in this field regards also the discovery of potent compounds bearing a morpholino group at R6. In fact, design of the previously reported ZK200775 (20, Fig. 5) (Ki ¼ 0.12 nM) derived from this extensive research, and was achieved by contemporary introducing the phosphonomethyl group at R4 and the morpholino substituent at R6.138,229,230 The design of LU115455 (33, Fig. 9) formally came from the hybridization of a R6-substituted derivative and a cycloalkyl fused C7 –C8 compound. LU115455, though lacking the EWG at R7, was a potent AMPA receptor antagonist showing also affinity for the KA receptor.269 Moreover, LU115455 was demonstrated to protect against convulsions in the kindling model, interestingly not showing unwanted effects on motor coordination.130,270 This result suggested a synergistic effect of combined antagonist action at AMPA and KA receptors, but also a larger safety window. 4. (Hetero)Cyclic-Fused Quinoxalinone Derivatives Tricyclic quinoxalinone compounds bearing the bridged (hetero)cyclic ring between C-5 and C-6, N4 and C-5, or C-3 and N-4 (Fig. 10) were extensively investigated. The C5-C6 bridged tricyclic derivatives include some of the most potent ‘‘in vitro’’ and ‘‘in vivo’’ receptor antagonists reported till now. The previously cited NBQX and PNQX (16 and 18, Fig. 5) belong to this large series.212,225 Several analogues of PNQX were synthesized, but none of them

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Figure 9. C-6 substituted quinoxalin-2,3-dione derivatives.

showed higher AMPA receptor affinity: modifications of the nitrogen atom position in the tetrahydropyridine ring, of the added unsaturated ring size, or of the substituent at the amine nitrogen gave, however, some compounds endowed with good affinity for the AMPA receptor, suggesting a steric tolerance in this region of the molecule.270,271 Due to the success obtained with NBQX and PNQX, others tricyclic C5-C6 bridged compounds were designed, some bearing a cycloalkyl fused ring suitably substituted269,272 and others with a substituted benzo ring similar to NBQX.273 The N-(6-nitro-2,3-dioxo-2,3,4,7,8,9-hexahydro-1Hcyclopenta[f]quinoxalin-8-yl)thiophene-3-carboxamide (34, Fig. 11) belonging to the C5–C6

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Figure 10. Template of the heterocyclic-fused quinoxalinone derivatives.

cycloalkyl fused tricyclic compounds,272 showed a broad spectrum of antagonist activity at the iGluRs, and neuroprotective and anticonvulsant properties. In order to control aqueous solubility and lipophilicity, most of these derivatives bear at R4 a polar hydrophilic group. The N4-C5 bridged derivatives were extensively studied,274–278 but most of them showed to be more selective for the Gly/NMDA receptor site than the AMPA ones. For example, SM18400 (35, Fig. 11) was a potent Gly/NMDA receptor antagonist which was reported to have efficacy in the MCAO model of epilepsy.276 The studies reported on this series of compounds have been useful in clarifying the selectivity requirements for the AMPA and Gly/NMDA receptors.276–278 The tricyclic C3-N4 bridged compounds were designed starting from the structural requirements suggested by reported AMPA pharmacophore models45,225,242 and with the aim of improving physicochemical properties that characterized most of the quinoxaline-2,3-dione derivatives. In fact, the low-water solubility was in part attributed to the presence of the 2,3-dione moiety. Thus, the oxygen atom at C-3 was replaced with a bioisosteric nitrogen atom as a constituent of the fused heterocyclic ring at C3-N4. This nitrogen atom, though more weakly, was considered to be able to function as a proton acceptor in the putative hydrogen-bond receptor-ligand interaction, thus profitably replacing the oxygen atom of the 3-carbonyl function of the quinoxalin-2,3-dione moiety. Several imidazo[1,2-a]quinoxalin-2-one derivatives242,279–282 and 1,2,4-triazolo[4,3-a]quinoxalin-4-one242,279,280,283–287 were reported in patent literature. Taking YM90K (Fig. 5) as lead compound, some tricyclic derivatives bearing an imidazole ring on the fused benzo moiety were designed.242,280–282,285–287 These compounds showed similar AMPA binding activity to YM90K, thus confirming the bioisosteric role of the N-3 nitrogen atom of the new tricyclic ring systems. Among the imidazoquinoxalinone series, the most active compound was the 1-ethyl-8-(imidazol-1yl)-7-nitroimidazo[1,2-a]quinoxalin-4(5H)-one (36a, Fig. 11) which showed high-AMPA receptor activity in the binding assay (Ki ¼ 20 nM). High-AMPA affinity and selectivity versus the Gly/ NMDA site was also found for the corresponding 1-unsubstituted compound 36b (Ki ¼ 57 nM).242,280 The same high-AMPA receptor affinity also characterized the 1,2,4-triazolo[4,3-a]quinoxalin-4one series. In fact, the 1-ethyl-7-nitro derivative 37a (Fig. 11), as well as in the imidazo[1,2-a] series, was the most potent compound among this series (Ki ¼ 48 nM), with the corresponding 1-unsubstituted derivative 37b endowed with a fivefold reduced AMPA binding affinity (Ki ¼ 190 nM).242,280 Subsequently, the 1-phosphonomethyl substituted compounds were reported to be potent AMPA receptor antagonists endowed with a neuronal injury inhibitor activity.284,286,287 The ‘‘in vivo’’ efficacy of these compounds was not reported in the open and patent literature. A contribution in this field was made by our research group at University of Florence, which reported extensive studies on a series of 4,5-dihydro-4-oxo-1,2,4-triazolo[1,5-a]quinoxaline-2-

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Figure 11. (Hetero)cyclic-fused quinoxalinone derivatives.

carboxylates (TQXs) bearing different substituents on the fused benzo moiety.288–291 These studies established that the presence of a N3-nitrogen containing heterocycle at position 8 of the TQX framework is an essential feature for potent and selective AMPA receptor antagonists. These 8-heterocyclic-substituted compounds were designed on the basis of a reported AMPA pharmacophore model242 and taking as lead compound the 7-chloro-8-nitro-4-oxo-1,2,4-triazolo[1,5-a]quinoxaline2-carboxylic acid 38, which was endowed with mixed AMPA-Gly/NMDA receptor activity.288 Early studies led to the discovery of both the 7-chloro-8-(1,2,4-triazol-4-yl)-2-carboxylic acid derivative TQX173 (39a, Fig. 11) (AMPA, Ki ¼ 0.14 mM; Gly/NMDA, Ki ¼ 33.5 mM) and its corresponding ethyl ester 39b (AMPA, Ki ¼ 0.70 mM; Gly/NMDA, I% (100 mM) ¼ 42) as the most active and selective compounds of the series,289,290 thus pointing out that the presence of the 8-(1,2,4-triazol-4yl) moiety led to more potent and selective AMPA antagonists than those bearing the claimed 8-(imidazol-1-yl) one.242 Further studies produced a great number of novel potent AMPA receptor antagonists291 and, among them, both the 7-nitro-8-(3-carboxypyrrol-1-yl)-2-carboxylic acid derivative 40a (AMPA, Ki ¼ 0.019 mM; Gly/NMDA, I% (100 mM) ¼ 7) and its corresponding ethyl ester 40b (AMPA, Ki ¼ 0.068 mM; Gly/NMDA, I% (100?mM) ¼ 16) were more potent and selective than TQX173. Moreover, compound 40b was highly selective for the AMPA receptor being totally inactive in both KA and Gly/NMDA receptor binding assays. Functional studies on NMDA and AMPA receptors were reported, confirming the antagonist activity of these derivatives. On the contrary, no data have been published on the pharmacological profile of this series, but investigations on the anticonvulsant activity are ongoing.

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C. Quinoxalin-2-One Derivatives The quinoxalin-2-one derivatives resulted from the development of previously described quinoxalin2,3-diones. First reported compounds showed Gly/NMDA receptor affinity,292 whereas more recent studies disclosed a series of 2-oxo-quinoxalin-3-carboxylic acid,293–297 and, among them, compound 41 (Fig. 12) was reported to inhibit [3H]AMPA binding with a Ki value of 700 nM.293 The 6-imidazo substituted derivative GRA293 (42, Fig. 12) was recently reported as potent, selective, and water-soluble AMPA receptor antagonist (Ki ¼ 22 nM, AMPA vs. Gly/NMDA selectivity >400).294,295 Novel 6-substituted-4-oxo-quinoxaline-3-carboxylic acid, bearing a trifluoromethyl group at position 7, were prepared in order to improve physicochemical properties. KRP199 (43, Fig. 12) was found to possess high potency (Ki ¼ 16 nM) and selectivity toward the AMPA receptor (AMPA vs. Gly/NMDA selectivity >600), and to have ‘‘in vivo’’ neuroprotective effects. SAR studies demonstrated that introduction of a trifluoromethyl group at position 7 maintains good biological activity and improves physicochemical properties with respect to the 7-nitro derivatives.152,296,297 Some analogues bearing phenylureido-substituted imidazole at position 6 of the quinoxalinone moiety were reported.294,296 D. Quinolin-2-Ones and Tricyclic Derivatives Modification of the quinoxalin-2,3-dione moiety yielded the corresponding quinolin-2-one analogues. Different EWG as potential hydrogen-bond accepting groups were introduced at position 3 of the quinoline ring system. The first compound of this series, reported as combined AMPA and Gly/NMDA receptor antagonist, was the 3-nitro-3,4-dihydro-2(1H)quinolin-2-one (L-698,544) (44, Fig. 13).298 Another similar approach led to the discovery of a series of 3-sulfonylamino derivatives with improved physicochemical properties. The 6,7-dinitro derivative 45 (Fig. 13) was found to have good AMPA receptor activity (IC50 ¼ 0.09 mM) and good AMPA versus Gly/NMDA receptor selectivity (IC50 ¼ 1.38 mM). However, compound 45 was devoid of any anticonvulsant activity.299 Several quinolin-2-ones were disclosed bearing polar substituents, such as nitro and carboxylate group, at position 3, and optionally substituted at position 4,298–305 but most of them preferentially bind the Gly/NMDA receptor site. Studies on these quinolin-2-one derivatives showed that the presence of a 3-carboxylic acid produced a high increase of AMPA receptors activity and selectivity. Moreover, selectivity was shifted toward AMPA receptor when nitro groups are present at position 6,7 on the fused benzo ring, whereas Gly/NMDA selectivity was favored by 5,7-dichloro ring substitution.305 Other reports on quinolin-2-one derivatives yielded potent AMPA receptor antagonists such as the 6,7-dichloro-2-oxo-1,2-dihydroquinoline-3-phosphonic acid (S17625) (46, Fig. 13). In addition of being a potent AMPA receptor ligand in binding assay, it was found to be active after oral administration in anticonvulsant and neuroprotective models.305,306 However, the development of this compound was stopped due to the nephrotoxicity manifested at therapeutic doses.

Figure 12. Quinoxalin-2-one derivatives.

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Figure 13. Quinolin-2-ones and tricyclic derivatives.

Recently, introduction of diverse sulfonyl moieties at position 6 of the fused benzo ring led to potent AMPA receptor antagonists with good ‘‘in vivo’’ activity and lower nephrotoxicity with respect to parent compounds.307–309 In fact, compound 47 showed promising profile in stroke models.309 Some 6-(hetero)aryl substituted compounds were evaluated for their binding at the AMPA receptors.310–312 Among them, compound 48 bearing a 4-(carboxyphenylcarbamoyloxy)methyl substituted imidazole at position 6 demonstrated to be a potent AMPA receptor antagonist.310 Fusion of the bicyclic quinoline ring system with an oxazole nucleus afforded a series of oxazolo[4,5-c]quinolin-2-one derivatives which were evaluated for their activity at iGluRs.313 These studies led to the identification of compound 49 showing high selectivity for the AMPA receptors. E. Quinazolin-2-Ones and Tricyclic Derivatives Recent research carried out in our laboratory disclosed the 3-hydroxy-quinazoline-2,4-dione as an useful scaffold to obtain selective AMPA and Gly/NMDA receptor antagonists.314 SAR studies on these derivatives confirmed that the presence of 1,2,4-triazol-4-yl substituent at position 6 of the quinazoline moiety is an important requisite in order to address selectivity toward the AMPA receptors. In fact, compound 50 (AMPA, Ki ¼ 0.25 mM; Gly/NMDA, Ki > 100 mM) was as active as TQX173 (39a, Fig. 11)289,290 at the AMPA receptors, but more selective. In the same laboratory, starting from the results obtained on the TQX series, a set of pyrazolo[1,5-c]quinazoline-2-carboxylates, variously substituted on the fused benzo moiety, was designed.315 The most active compound of this series was the 8-chloro-9-(1,2,4-triazol-4-yl) derivative 51 (AMPA, Ki ¼ 0.14 mM; Gly/NMDA, Ki ¼ 8.3 mM), which showed lower AMPA versus Gly/NMDA selectivity than the analogue lead compound TQX173, but was equiactive at the AMPA receptors. Other tricyclic derivatives that have to be mentioned, belong to the large family of 1,2,4triazolo[1,5-c]quinazolines which, however, take their rightful place among the Gly/NMDA receptor antagonists. Some derivatives of this series were first reported by BASF.316,317 Among them,

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Figure 14. Quinazolin-2-ones and tricyclic derivatives.

compound 52 was claimed to be an AMPA receptor antagonist with potential efficacy as an anticonvulsant agent.316 More attractive was the 8-nitro-9-(imidazol-1-yl) derivative Ro48-8587 (53, Fig. 14) which showed a high degree of selectivity toward the AMPA receptors and very high potency as well: in fact, it demonstrated to have ‘‘in vivo’’ anticonvulsant properties and to be moderately neuroprotective in the MCAO model of focal brain ischaemia. For its interesting profile, Ro 48-8587 was radiolabeled, becoming a useful tool for studies on the AMPA receptors.318 F. Imidazoindenopyrazines A heterogeneous class of tetracyclic derivatives structurally related to C3-N4 bridged quinoxaline2,3-diones (Fig. 10) was reported. Compounds of these series were generally nonselective AMPA versus Gly/NMDA receptor antagonists, but were demonstrated to have anti-ischaemic and neuroprotective properties,319–334 and, most importantly, low toxicity. Optimization of both the 10H-imidazo[1,2-a]indeno[1,2-e]pyrazin-4-one328,335 (54, Fig. 15) and the corresponding 9-acetic acid derivative 55,331 which were reported as mixed AMPA and Gly/

Figure 15. Imidazoindenopirazine derivatives.

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NMDA receptor antagonists, led to the identification of high-affinity derivatives with improved selectivity and ‘‘in vivo’’ potency.327–335 In fact, both the 2-carboxylic acid derivatives 56 and the analogue RPR117824 (57, Fig. 15) were two of the most interesting compounds of this series showing high affinity and selectivity for the AMPA receptors.334,335 Further studies demonstrated that RPR117824 was one of the most potent anticonvulsant agent in the MES test described so far. It showed to be active also in both the PTZ-induced convulsions and in the DBA/2 mice tests.52 This high ‘‘in vivo’’ activity could be in part ascribed to its good physicochemical properties: in fact, it was endowed with improved water solubility and duration of action with respect to the parent quinoxalinedione compounds. As a part of a program aimed at improving AMPA receptor affinity and selectivity of the parent compounds 55, 56, the Mignani group developed a large number of imidazoindenopyrazine derivatives and, among them, 8-methylureido-10-acetic acid derivative 58 should be mentioned. The racemic 58 was resolved into the two isomer: the dextrorotatory isomer (þ)-58 displayed a 10-fold higher potency (IC50 ¼ 0.004 mM) at the AMPA receptors than the levo one (IC50 ¼ 0.039 mM), while both isomers showed high AMPA versus Gly/NMDA receptor selectivity.328 Subsequently, the 2-phosphonic acid derivative 59, bearing a 9-(tetrazol-5-yl)methyl substituent, was demonstrated to have a similar pharmacological profile to RPR117824.332 This compound belongs to a large series of indenone analogues which ensued from bioisosteric replacements of the 2- and 9-substituents of the indenone nucleus of RPR117824. Most of the disclosed derivatives showed to be potent AMPA receptor antagonists capable of penetrating the blood–brain barrier.328–334 SAR studies indicated that both the position and the nature of the substituent on the tetracyclic ring system are crucial for the AMPA receptor–ligand interaction. G. Isatinoxime Derivatives Early work in this research area reported compounds NS102 and NS257 (60 and 61, Fig. 16) as AMPA receptor antagonists.336–339 Replacement of the C6-C7 bridged ring of NS102 with heterocycles gave a vast number of new isatinoxime derivatives with different degree of potency and selectivity.340–343

Figure 16. Isatinoxime derivatives.

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On the basis of the above reported pharmacophore model on quinoxaline-2,3-dione template (Fig. 6), the activity of this class of derivatives was ascribed to the bioisosteric role of the C-2 carbonyl and the C-3 oxime moieties for the crucial coulombic interaction with the putative cationic proton donor site of the receptor.45,225,242 In fact, these derivatives and quinoxalinedione compounds can be considered as structural analogues, whose recent development has often followed parallel courses. Compound 62 (Fig. 16), which was the lead compound for the developing of NS257, was the first AMPA receptor antagonist to demonstrate anticonvulsant activity after oral administration, although having low water solubility.337 On the contrary, the derived NS257 was not orally active, but it was demonstrated to be as potent as NBQX against AMPA-induced convulsions after i.v. administration,52 and to have selectivity ‘‘in vitro’’ and ‘‘in vivo’’ for blocking AMPA-induced toxicity.339 Recently, some newly synthesized isatinoxime derivatives were claimed as competitive AMPA receptor antagonists endowed with significant neuroprotective activity both in cerebral ischaemia and seizure model.343–345 One of the most interesting compounds is represented by SPD502 (63, Fig. 16)343 which was characterized by both the N,N-dimethyl-benzensulfonamide moiety on the fused benzo ring and an hydrophilic side chain on the oxime oxygen. This compound was designed in order to find more potent and selective AMPA antagonists, but, mainly, to discover a new compound with increased water solubility and, thus, prolonged effect.346 SPD 502, which belongs to the second generation of isatinoximes, was demonstrated to be very selective toward the AMPA receptor, while it showed no affinity for KA and Gly/NMDA sites. Moreover, it was anticonvulsant in the MES test52 and demonstrated efficacy in a rat permanent MCAO model. Since SPD502 seems to posses a suitable profile in models of neuroprotection, it can be considered as a drug candidate for the treatment of ischaemic injury.347,348

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307. Adir Et Compagnie. 6-Sulfamoyl-3-quinolylphosphonic acid derivatives, method of preparation, pharmaceutical compositions containing them and use as inhibitors of AMPA receptors. 2001; EP 1125941. 308. Adir Et Compagnie. 6-Aminosulfonyl or 6-hydrazinosulfonyl-3-quinolylphosphonic acid derivatives, method of preparation, pharmaceutical compositions containing them and use as inhibitors of AMPA receptors. 2001; EP 1125942. 309. Cordi AA, Desos P, Ruano P, Al-Badri H, Fugier C, Chapman AG, Meldrum BS, Thomas J-Y, Roger A, Lestage P. Novel quinolone-phosphonic acid AMPA antagonists devoid of nephrotoxicity. Il Farmaco 2002;57:787–802. 310. Kyorin Pharm. Co. LTD. Preparation of quinoline carboxylic acid derivatives as AMPA receptor antagonists. 2000; WO 2000050416. 311. Kyorin Pharm. Co. LTD. Preparation of 6-arylquinolinecarboxylic acid derivatives. 2000; JP 2000169450. 312. Kyorin Pharm. Co. LTD. Preparation of 6,7-disubstituted quinolinecarboxylic acid derivatives. 2000; JP 12169451. 313. Kyorin Pharm. Co. LTD. Preparation of tricyclic compounds as AMPA receptor antagonists. 2001; WO 2001046190. 314. Colotta V, Catarzi D, Varano F, Calabri FR, Filacchioni G, Costagli C, Galli A. 3-Hydroxy-quinazoline2,4-dione as a useful scaffold to obtain selective Gly/NMDA and AMPA receptor antagonists. Bioorg Med Chem Lett 2004;14:2345–2349. 315. Varano F, Catarzi D, Colotta V, Filacchioni G, Costagli C, Galli A, Carla` V. Synthesis and biological evaluation of a new set of pyrazolo[1,5-c]quinazoline-2-carboxylates as novel excitatory amino acid antagonists. J Med Chem 2002;45:1035–1044. 316. Basf AG. Preparation of triazoloquinazolines as nervous system agents. 1994; DE 4241563. 317. Basf AG. Preparation of triazoloquinazolines as nervous system agents. 1994; DE 4241564. 318. Mutel V, Trube G, Klingelschmidt A, Messer J, Bleuel Z, Humbel U, Clifford M, Ellis GJ, Richards JG. Binding characteristics of a potent AMPA receptor antagonist [3H]Ro 48-8587 in rat brain. J Neurochem 1998;71:418–426. 319. Rhone-Poulenc Rorer SA. Preparation of 5H,10H-imidazo[1,2-a]indeno[1,2-e]pyrazin-4-ones as AMPA and NMDA receptor antagonists. 1994; WO 9407893. 320. Rhone-Poulenc Rorer SA. Preparation of imidazoindenopyrazinones as AMPA and NMDA receptor antagonists. 1995; WO 9526349, 9526350. 321. Rhone-Poulenc Rorer SA. Preparation of spiro(heterocycle-imidazo[1,2-a]indeno[1,2-e]pyrazine)-4 0 ones as AMPA and NMDA receptor antagonists. 1996; WO 9614318. 322. Rhone-Poulenc Rorer SA. Preparation of 5H,10H-imidazo[1,2-a]indeno[1,2-e]pyrazin-4-ones as AMPA and NMDA receptor antagonists. 1996; WO 9631511. 323. Rhone-Poulenc Rorer SA. Preparation of 5H,10H-imidazo[1,2-a]indeno[1,2-e]pyrazine-2-carboxylates as AMPA and NMDA receptor antagonists. 1996; WO 9602544. 324. Rhone-Poulenc Rorer SA. 2-Substituted 5H,10H-imidazo[1,2-a]indeno[1,2-e]pyrazin-4-ones useful as AMPA and NMDA receptor antagonists, their preparation, and drug containing them. 1997; WO 9725326. 325. Rhone-Poulenc Rorer SA. 5H,10H-Imidazo[1,2-a]indeno[1,2-e]pyrazin-4-one derivatives, useful as AMPA and NMDA receptor antagonists, their preparation, and drug containing them. 1997; WO 9725327. 326. Rhone-Poulenc Rorer SA. 2-Substituted 5H,10H-imidazo[1,2-a]indeno[1,2-e]pyrazin-4-ones useful as AMPA and NMDA receptor antagonists, their preparation and intermediates, and drug containing them. 1997; WO 9725328. 327. Jimonet P, Boireau A, Cheve´ M, Damour D, Genevois-Borella A, Imperato A, Pratt J, Randle JCR, Ribeill Y, Stutzmann J-M, Mignani S. Spiro-imidazo[1,2-a]indeno[1,2-e]pyrazin-4-one derivatives are mixed AMPA and NMDA glycine-site antagonists active in vivo. Bioorg Med Chem Lett 1999;9:2921–2926. 328. Mignani S, Bohme GA, Boireau A, Cheve´ M, Damour D, Debono M-W, Genevois-Borella A, Imperato A, Jimonet P, Pratt J, Randle JCR, Ribeill Y, Vuilhorgne M, Stutzmann J-M. 8-Methylureido-4,5-dihydro-4oxo-10H-imidazo[1,2-a]indeno[1,2-e]pyrazines: Highly potent in vivo AMPA antagonists. Bioorg Med Chem Lett 2000;10:591–596. 329. Jimonet P, Cheve´ M, Bohme GA, Boireau A, Damour D, Debono M-W, Genevois-Borella A, Imperato A, Pratt J, Randle JCR, Ribeill Y, Stutzmann J-M, Vuilhorgne M, Mignani S. 8-Methylureido-10-amino-10methy-imidazo[1,2-a]indeno[1,2-e]pyrazine-4-ones: Highly in vivo potent and selective AMPA receptor antagonists. Bioorg Med Chem 2000;10:2211–2217. 330. Stutzmann J-M, Bohme GA, Boireau A, Damour D, Debono M-W, Genevois-Borella A, Imperato A, Jimonet P, Pratt J, Randle JCR, Ribeill Y, Vuilhorgne M, Mignani S. 4,10-Dihydro-4-oxo-4H-imidazo[1,2a]indeno[1,2-e]pyrazin-2-carboxylic acid derivatives: Highly potent and selective AMPA receptor antagonists with in vivo activity. Bioorg Med Chem Lett 2000;10:1133–1137.

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331. Pratt J, Jimonet P, Bohme GA, Boireau A, Damour D, Debono M-W, Genevois-Borella A, Randle JCR, Ribeill Y, Stutzmann J-M, Vuilhorgne M, Mignani S. Synthesis and potent anticonvulsant activities of 4oxo-imidazo[1,2-a]indeno[1,2-e]pyrazin-8- and 9-carboxylic (acetic) acid AMPA antagonists. Bioorg Med Chem Lett 2000;10:2749–2754. 332. Jimonet P, Bohme GA, Bouquerel J, Boireau A, Damour D, Debono M-W, Genevois-Borella A, Hardy J-C, Hubert P, Manfre´ F, Nemecek P, Pratt J, Randle JCR, Ribeill Y, Stutzmann J-M, Vuilhorgne M, Mignani S. Bioisosteres of 9-carboxymethyl-4-oxo-imidazo[1,2-a]indeno[1,2-e]pyrazin-2-carboxylic acid derivatives, Progress towars selective, potent in vivo AMPA antagonists with longer duration of action. Bioorg Med Chem Lett 2001;11:127–132. 333. Stutzmann J-M, Bohme GA, Boireau A, Damour D, Debono M-W, Genevois-Borella A, Jimonet P, Pratt J, Randle JCR, Ribeill Y, Vuilhorgne M, Mignani S. Synthesis of anticonvulsive AMPA antagonists: 4-oxo10-substituted-imidazo[1,2-a]indeno[1,2-e]pyrazin-2-carboxylic acid derivatives. Bioorg Med Chem Lett 2001;11:1205–1210. 334. Mignani S, Bohme GA, Guillaume B, Boireau A, Jimonet P, Damour D, Debono M-W, Genevois-Borella A, Pratt J, Vuilhorgne M, Wahl F, Stutzmann J-M. 9-Carboxymethyl-5H,10H-imidazo[1,2-a]indeno[1,2e]pyrazin-4-one-2-carboxylic acid (RPR117824): Selective, anticonvulsive and neuroprotective AMPA antagonists. Bioorg Med Chem 2002;10:1627–1637. 335. Mignani S, Aloup J-C, Barreau M, Blanchard JC, Bohme GA, Andrees G, Boireau A, Damour D, Debono M-W, Dubroeucq M-C, Genevois-Borella A, Imperato A, Jimonet P, Pratt J, Randle JCR, Reibaud M, Ribeill Y, Stutzmann J-M. Synthesis and pharmacological properties of 5H,10H-imidazo[1,2a]indeno[1,2-e]pyrazin-4-one, a new competitive AMPA/KA receptor antagonist. Drug Dev Res 1999;48:121–129. 336. Neurosearch A/S. Preparation of isatin derivatives as central nervous system (CNS) agents. 1991; EP 432648. 337. Watjen F, Nielsen EO, Drejer J, Jensen LH. Isatin oximes—A novel series of bioavailable non-NMDA antagonists. Bioorg Med Chem Lett 1993;3:105–106. 338. Neurosearch A/S. Preparation of benzodipyrrolediones and analogs as excitatory amino acid antagonists. 1993; EP 529636. 339. Watjen F, Bigge CF, Jensen LH, Boxer PA, Lescosky LJ, Nielse EO, Malone TC, Campbell CW, Coughenour LL. NS257 (1,2,3,6,7,8-hexahydro-3(hydroxymino)-N,N,7-trimethyl-2-oxobenzo[2,1b:3,4-c]dipyrrole-5-sulfonamide) is a potent, systemically active AMPA receptor antagonist. Bioorg Med Chem Lett 1994;4:371–376. 340. Neurosearch A/S. Isatin oxime derivatives, their preparation and use as antagonists of excitatory amino acids at the AMPA receptor. 1995; US 5436250. 341. Neurosearch A/S. Preparation of isatin oxime derivatives for treatment of central nervous system disorders. 1995; EP 633262. 342. Neurosearch A/S. Fused indole and quinoxaline derivatives as glutamate antagonists. 1996; WO 9608495. 343. Neurosearch A/S, Watjen F, Drejer J. Preparation of novel indole-2,3-dione-3-oximes as glutamate receptor antagonists. 1998; WO 9814447. 344. Neurosearch A/S. Preparation of fused indole-2,3-dione-3-oximes for treatment of disorders associated with release of excitatory amino acids. 1999; WO 9949864. 345. Neurosearch A/S. A method of preparing enantiomrrs of indole-2,3-dione-3-oxime derivatives. 2004; WO 2004018466. 346. Nielsen EO, Varming T, Mathiesen C, Jensen LH, Moller A, Gouliaev AH, Watjen F, Drejer J. SPD 502: A water-soluble and in-vivo long lasting AMPA antagonist with neuroprotective activity. J Pharm Exp Ther 1999;289:1492–1501. 347. McCracken E, Fowler JH, Dewar D, Morrison S, McCulloch J. Grey matter and white matter iscemic damage is reduced by the competitive AMPA receptor antagonist, SPD 502. J Cerebr Blood Flow Metab 2002;22:1090–1097. 348. Fowler JH, McCracken E, Dewar D, McCulloch J. Intracerebral injection of AMPA causes axonal damage in vivo. Brain Res 2003;991:104–112. Daniela Catarzi received her degree in Pharmaceutical Chemistry and Technology in 1990, and her Ph.D. in Medicinal Chemistry in 1993. Both degrees were obtained at the University of Florence, Italy, where she has held the position of Assistant Professor of Medicinal Chemistry since 1998. Early research focused on the identification of benzodiazepine receptor ligands and GABAA receptor antagonists. In recent years, her attention has been directed toward the development of both adenosine and glutamate receptor antagonists, which represent possible new therapeutical strategies for the treatment of neurodegenerative diseases.

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Vittoria Colotta received her degree in Pharmaceutical Chemistry and Technology in 1985 and her Ph.D. in Medicinal Chemistry in 1988 from the University of Florence. Between 1991 and 2001, she was Assistant Professor of Medicinal Chemistry at the University of Florence and since November 2001 she is Associate Professor of Medicinal Chemistry at the University of Florence. Her research has been addressed to the study of central benzodiazepine receptor ligands and GABAA receptor antagonists. More recently, her interest has been focused on antagonists of adenosine and glutamate receptors. Flavia Varano received her degree in Pharmaceutical Chemistry and Technology in 1995 and her Ph.D. in Medicinal Chemistry in 1999 both at the University of Florence. Since September 2000, she is Assistant Professor of Medicinal Chemistry at the University of Florence. She has developed her scientific activity in the field of medicinal chemistry, particularly in the design, synthesis and structure activity relationship studies of adenosine and glutamate receptor antagonists.