Current Topics in Medicinal Chemistry 2005, 5, 31-42
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AMPA Receptor Antagonists as Potential Anticonvulsant Drugs Giovambattista De Sarro1, Rosaria Gitto2, Emilio Russo1, Guido Ferreri Ibbadu1, Maria Letizia Barreca2, Laura De Luca2 and Alba Chimirri2,* 1
Chair of Pharmacology, Department of Experimental and Clinical Medicine, Faculty of Medicine and Surgery, University of Catanzaro, Italy, 2 Department of Medicinal Chemistry, Faculty of Pharmacy, University of Messina, Italy. Abstract: Over the last years α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid glutamate receptors (AMPARs) have been intensively studied owing to their crucial role in physiological and pathological processes. Efforts targeting AMPAR have been focused on identification of ligands as potential therapeutic agents useful in the prevention and treatment of a variety of neurological and non-neurological diseases. In particular, extensive work was addressed to the discovery of selective antagonists some of which proved to be potent anticonvulsant agents.
Key Words: Glutamate, AMPA receptor antagonists, AMPAR, anticonvulsants. 1. INTRODUCTION Approximately 1% of the world’s population (~50 million people) is affected by epilepsy, a serious neurological disorder that typically manifests as spontaneous convulsions and/or a loss of consciousness. These symptoms are caused by the appearance of abnormal electrical seizure discharges, characterized by episodic high frequency firing of impulses by a group of neurones within the brain as a result of an imbalance between excitatory and inhibitory synaptic processes [1]. Often, therapeutic regimens for epileptic patients will involve a change of first-line and/or add-on antiepileptic drugs. Most antiepileptic drugs are associated with adverse effects, such as sedation, ataxia and weight loss (e.g. topiramate) or weight gain (e.g. valproate, tiagabine, and vigabatrin). Rare adverse effects can be life threatening such as rashes leading to Stevens-Johnson syndrome (e.g. lamotrigine) or aplastic anaemia (e.g. felbamate) [2]. As about 30 % of people affected by epilepsy have uncontrolled seizures, the development of safer and more effective new antiepileptic drugs (AEDs) is necessary. Despite the excitement that has accompanied the launch of new alternative drugs in the last 20 years, they have made little improvement on the number of patients who suffer from chronic and refractory epilepsy [1,3,4]. The role of novel drugs in the treatment of newly diagnosed epilepsy is not completely clear at this point, because their chronic sideeffects and their efficacy in refractory epilepsy have not yet been established. More than 100 neurotransmitters or neuromodulators have been shown to play a role in neuronal processes. Some specific neurotransmitters that relate to epilepsy are γaminobutyric acid (GABA), norepinephrine, endogenous opioid peptides, and the excitatory amino acids, such as glutamate (1) and aspartate, although the most widely
studied have been GABA and glutamate acting at more than half the neuronal synapses in the brain [5]. Present clinically efficacious antiepileptics act by inducing prolonged inactivation of the Na+ channel, by blocking Ca2+ channel currents or by enhancing inhibitory GABAergic neurotransmission. Some of the “newer” anticonvulsant agents act via a number of different mechanisms, which may include antagonism of glutamatergic neurotransmission [6]. Glutamatergic neurotransmission involves ionotropic and metabotropic receptors (iGluRs and mGluR) that are activated under differing circumstances. The iGluRs are ligand gated ion channels which are further subdivided into three classes based on their affinity for specific agonists: the N-methyl-D-aspartic acid (NMDA, 2) , the kainic acid (KA, 3) and α-amino-3-hydroxy-5methyl-4-isoxazolepropionic acid (AMPA, 4) receptor subtypes allow for sodium, potassium and calcium flux upon glutamate binding. HO 2C
C O2 H NH
HO 2C
CO2H NHCH 3
2
1 (S )-Glutamic acid
2 NMDA
CH3 CO2H
C H2
N H
HO2 C
CO2H
3 Kaini c aci d
OH H2N CH3
N O
4 AMP A
Fig. (1). iGluR agonists. *Address correspondence to this author at Dipartimento Farmaco-Chimico, Facoltà di Farmacia, Università di Messina, Viale Annunziata I-98168 Messina, Italy; Tel: +39 0906766412; Fax: +39 090355613; E-mail:
[email protected] 1568-0266/04 $??.00+.00
The iGluRs comprise of different subunits which present different distribution in the brain: NR1, NR2A-D, NR3A-B (NMDA), GluR1-4 (AMPA) and GluR5-7, KA1-2 (KA) (Figure 2) [7]. © 2005 Bentham Science Publishers Ltd.
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Fig. (2). Glutamate receptors.
Initially, it was thought that synaptically released glutamate acted only on iGluRs opening cation-permeable channels. However, from 1985 onwards, evidence accumulated that glutamate, like acetylcholine, dopamine, serotonin, and noradrenaline, could also act via G-proteincoupled mGluRs to induce phosphoinositide hydrolysis [8,9] or to decrease adenylate cyclase activity [10]. Since the cloning and sequencing of mGlu1 in 1991 [11] seven other mGluRs have been characterised and sequenced. These eight receptors, termed mGluR1-8, fall into three groups according to their sequence homology, transduction mechanisms and agonist pharmacology [12]. In general, mGluRs modulate glutamatergic excitations by pre-synaptic, post-synaptic and glial mechanisms (Figure 2). 2. AMPA RECEPTORS AMPA glutamate receptors (AMPARs) have structural features that allow for multiple sites to which ligands can act to modulate receptor functions [13]. AMPARs are tetramers built from closely related subunits, called both GluR1-4 and GluRA-D [14], assembled from homo- or heteromeric complexes surrounding a central cation-conducting pore mediating fast excitatory postsynaptic potentials by the flux of Na+ and Ca2+ ions [15]. Release of glutamate from the presynaptic neuron and its binding to AMPA receptors of the postsynaptic neuron leads to cations influx into the cells, but also causes the receptor to desensitize thus preventing excitotoxic processes. Each of GluR1-4 subunit can exist as two forms, flip and flop, due to variable gene splicing and consists of a long extracellular amino terminus, jointed to three transmembrane spanning domains (TM1, TM3 and TM4), a membrane imbedded re-entry loop (M2) that connects TM1 and TM3, and a short intracellular C-terminus as showed in Figure 3 for GluR2. Two discontinuous extracellular domains (S1S2) contain the glutamate binding site, responsible for binding both the neurotransmitter and the competitive agonists/ antagonists [16]. The application of X-ray diffraction has allowed the structure of the GluR2 bound with a series of competitive agonists/antagonists to be determined, providing some details of ligand recognition and of the activation/ deactivation mechanism [17]. On the contrary, no X-ray structure of any complex between non-competitive antagonists and their binding site has been reported. Therefore an homology model study has been recently carried out in the attempt to decipher the mechanism of
action and the localization of the binding pocket for AMPAR allosteric modulators [18]. It has been hypothesized that AMPA and NMDA receptors have similar structural organization and that, similarly to the allosteric binding site of NMDA antagonists [19], the distal N-terminus region might have the binding site for AMPAR non-competitive ligands. The results of homology modelling and molecular docking experiments identified the LIVBP-like region in the N-terminal domain as a plausible binding site and indicated the bind mode and the preferred disposition of AMPAR allosteric ligands. Moreover, it has been postulated the presence of at least other two binding-sites: a polyamine recognition site within the ion channel for a particular group of antagonists and an allosteric site, different to that of positive modulators, at which non-competitive antagonists can bind [20]. The present review is addressed to AMPAR antagonists with particular attention to molecules effective for treatment and prevention of epileptic seizures. 3. COMPETITIVE AMPA RECEPTOR ANTAGONISTS Quinoxaline derivatives are an interesting class of specific and potent competitive non-NMDA glutamate receptor antagonists [13,20,21]. Some quinoxaline-2,3-
Fig. (3). GluR2 subunit of AMPA receptor.
AMPA Receptor Antagonists as Potential Anticonvulsant Drugs
Current Topics in Medicinal Chemistry, 2005, Vol. 5, No. 1
diones such as DNQX (5), NBQX (6), YM-90K (7), YM872 (8) have been found to be neuroprotective in various models of ischemia and to have anticonvulsant properties in different models of epilepsy.
O2N
H N
O
O2N
N H
O
H2NO 2S O2N
5, DNQX
H N
O
N H
O
R N
N
O
O 2N
N H
O
7 R =H, YM90K 8 R = CH2C O2 H, YM872
Fig. (4). Quinoxalinedione derivatives.
Using these molecules as templates the synthesis of different quinoxaline derivatives was thus pursued, together with extensive structure activity relationships (SAR) and pharmacophore modelling studies on this class of compounds. Recently, the X-ray structure of the competitive antagonist ATPO in complex with the GluR2 ligand-binding core has been solved and compared with the only previous complex with DNQX. It has been thus observed that noncovalent interactions between the two molecules and the receptor subunit stabilize an open form of the ligand-binding core, contrarily to agonists which induce substantial domain closure [17,22]. Molecular modelling studies were also performed with the aim to highlight the key residues involved in ligand recognition and to estimate the differences of binding mode between agonists and antagonists. CH3
H2O3P
N
H3C O2S CH3
O2 N
H N
O
N H
O
H N
O2 N
9
H N
O
N H
O
10, AM P397A O
Furthermore it has also been demonstrated that the presence of suitable substituents on the quinoxaline skeleton influenced the selectivity against iGluRs as well as pharmacokinetic properties. In particular, some 5-aminoalkyl substituted quinoxaline-2,3-diones were reported as AMPA receptor antagonists, where their affinity is depending upon the orientation of substituent. For instance, compound 9 showed efficacy in maximal electroshock seizures but did not show selectivity between AMPA and kainate receptors [23]. In order to increase the water solubility of these derivatives, an acidic functionality has been introduced thus affording the identification of {[(7-nitro-2,3-dioxo1, 2, 3, 4 - tetrahydro - quinoxalin-5-ylmethyl)-amino]-methyl}phosphonic acid (10, AMP397A). This compound displayed high affinity ([3H]CNQX binding, IC50=11 nM) and selectivity for AMPAR. Moreover, AMP397A showed good in vivo potency in different animal models and oral activity as anticonvulsant agent (Table 1) [24].
6, NBQX
N
33
Some novel fused 2,3-quinoxalines were obtained as potential therapeutic agents for the treatment of epilepsy, among which compound 11 proved to be antagonist of AMPA and kainate receptors, with IC50 binding affinity values of 0.24 µM and 1.62 µΜ, respectively [25] and active in the maximal electroshock seizure (MES) assay in mice. Table 1.
Anticonvulsant (AMP397A).
Properties
of
Compound
10
ED50(mg/kg) MES
9.0 po
PTZ
14.0 ip
Audiogenic seizures
5.4 po
The syntheses of a series of 6,7-disubstituted-2-(1H)oxoquinolines bearing different acidic functions in the 3-position and their salts have also been reported. In particular, 6,7-dichloro-2-(1H)-oxoquinoline-3-phosphonic acid (S17625, 12) was a potent, water soluble and selective AMPA antagonist but nephrotoxic and without anticonvulsant effects [26]. More recently, exploiting SAR it was demonstrated that the replacement of chlorine in position 6 by a sulfonylamine moiety led to very potent AMPA antagonists endowed with good in vivo activity and lacking nephrotoxicity potential. Compounds 13 and 14 manifested significant anticonvulsant efficacy in audiogenic seizures in DBA/2 mice when compared with NBQX (Table 2) [27].
N O
O2 N
H N
O
N H
O
11
Fig. (5). Quinoxalinedione derivatives.
PO3H2
Cl
Cl
N H
R
O S
COOH
N H
O
12, S 17625
Fig. (6). 2-Oxoquinoline derivatives.
Cl
N H 13 R = H 14 R = NHCOP h
O
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Table 2.
Anticonvulsant Seizures.
Efficacy
Against
Audiogenic
cpd
ED50 (mg/kg)
13
3.32
14
3.00
NBQX
12.6
A new series of hydrosoluble AMPAR antagonists containing 4, 5 - dihydro - 4 - oxo - 10H - imidazo[1,2-a]indeno [1,2-e]pyrazine system have been synthesized [28-34]. SAR studies demonstrated that both the position and the nature of the substituents on the tetracyclic skeleton influence the activity. Particularly advantageous is the presence of the carboxy substituent or its bioisosters such as tetrazole or phosphonic acid groups at 2 and 9 positions. Compounds 15 (RPR119990), 16 (RPR117824) and 17 exhibited potent anticonvulsant effects following ip and iv administration and are considered members of a new generation of AMPA antagonists with high solubility and better duration of action than quinoxalinedione series (Table 3). R
HO 2C
N
N
N H
O
15, R = PO3H2, R PR-119990 16, R = CO2H, RP R-117824 P O3H2
HN
N
N
N
N
N H
O
N
17
Fig. (7). Imidazo[1,2-a]indeno[1,2-e]pyrazines. Table 3.
Anticonvulsant Efficacy Against MES Test.
cpd
ED50 (mg/kg, ip)
15
3.5
16
1.2
17
1.0
YM-90K
12.0
NBQX
36.0
Chimirri et al.
4. NON-COMPETITIVE ANTAGONISTS The non-competitive AMPAR antagonists, interacting with an allosteric AMPA binding site, have the advantage of remaining effective independently of the level of glutamate or the polarization state of the synaptic membrane during a neurological diseases [20,35]. Moreover, they do not influence the normal glutamatergic activity also after prolonged use. Thus, in recent years some important classes of these ligands have been developed. The first non-competitive AMPA antagonist was 1 - (4 - aminophenyl) - 4 - methyl - 7,8 - methylenedioxy-5H-2,3benzodiazepine (GYKI 52466, 18) [36], discovered in 1989 and used as template to develop novel more potent and less toxic AMPAR modulators (Figure 8). In detail, 3-Nsubstituted 3,4-dihydro-2,3-benzodiazepine analogues have been developed to prevent the excitotoxic action of high extracellular glutamate levels [37,38]. The importance of stereoselectivity in AMPA receptor recognition is also confirmed by the higher activity of R-enantiomers such as (-) GYKI 53733 (19, also named LY300164 or talampanel) and (-)GYKI 53784 (20) [39,40]. Talampanel emerged as highly active molecule and is currently under phase II clinical trials in the US in patients with severe epilepsy not responsive to other drugs [41]. Animal studies have shown it to have a broad spectrum of anticonvulsant activity. Its mean plasma half life is about 7 hours, the protein binding ranges from 67 to 88%, and moreover the plasma concentrations are affected by acetylator status [42]. It is an irreversible inhibitor of CYP3A and so may increase concentrations of concomitantly administered carbamazepine. A double-blind, placebo-controlled add-on trial in 49 patients with refractory partial epilepsy showed a mean seizure reduction of 21% compared with placebo. Dizziness and ataxia were the most common adverse effects [42]. Other derivatives were synthesized by introducing different functionalities on the 2,3-benzodiazepine system (21-23) obtaining more active, less toxic and longer lasting anticonvulsant agents [43-53]. These results showed that the introduction of a lactam function and the modification of the methylenedioxy moiety were well-tolerated by AMPA receptor. Furthermore, while compounds with either a methoxy or an halogen group at 8position retained considerable AMPA antagonist potency, the introduction of the same substituents at 7-position negatively influenced the anticonvulsant activity [35]. The solid phase synthesis techniques have also been successfully applied to the preparation of 1-aryl-7,8-dimethoxy-3,5dihydro-2,3-benzodiazepin-4-ones [54]. The synthesis of several 2,3-benzodiazepines containing an additional heterocyclic ring fused to the “c” edge of the 7membered diazepine system allowed the discovery of new non-competitive AMPA receptor antagonists such as imidazo-2,3-benzodiazepine derivative 24 (GYKI 47621) and the triazolo-2,3-benzodiazepines which demonstrated interesting pharmacological properties [44,45,55-57]. SAR studies emphasized that appropriate chemical features able to participate in hydrogen bond interactions are
AMPA Receptor Antagonists as Potential Anticonvulsant Drugs
Current Topics in Medicinal Chemistry, 2005, Vol. 5, No. 1
Me
Me R
O
R3
1
N O
N
N
R
O
N
2
H 2N
H2 N
18, GYKI 52466
(-) 19, R 1-R 2 = -OCH2O-; R 3 = Me GYKI 53733 talam panel (-) 20, , R 1 -R 2 = -OCH 2O-; R3 = NHMe GYKI53784 (-) 21, R1 = H, R2 = C l, R3 = H, R3 = Me
O
N
Me
N
R1
MeO N
NH N
R2
35
H 2N
N
N
Cl
N
MeO
H2N
22, CF M-2 R1 = R2 = MeO 23, R1 - R 2 = -OCH 2O-
NH O
Br
24, GYKI 47621
25
Fig. (8). 2,3-Benzodiazepine derivatives.
key structural requirements for the anticonvulsant activity of this class of molecules. In particular, 6-(4’-bromophenyl)-8,9-dimethoxy-11H[1,2,4]triazolo[4,5-c][2,3]benzodiazepine-3(2H)-one (25) was almost 10-fold more active than GYKI 52466 (18), and 3.5fold more than CFM-2 (22) and talampanel (19) in audiogenic seizure test, acting via negative allosteric modulation of the AMPA receptor as confirmed by electrophysiological tests [57]. Taking the 2,3-benzodiazepine derivatives as a mould, different arylphthalazines have been developed as negative AMPAR modulators [58-62]. It was reported that some molecules, such as SYM 2206 (26) and SYM 2189 (27), demonstrated efficient protection of both mice and rats in MES test (35 and 52 mg/kg ip respectively). Moreover, 4aryl-1,2-dihydrophthalazin-1(2H)-one derivatives (28 and Me R
R
1
Other non-competitive AMPAR antagonists containing quinazolin-4-one skeleton were developed by Pfizer research group [63-68]. Compound CP-465,022 (+)-(aS)-(2chlorophenyl) - 2 - [(E) - 2 - [6 - (diethylaminomethyl)pyridin-2yl]-vinyl]-6-fluoroquinazolin-4(3H)-one 30 was tested in different pharmacological assays and showed anticonvulsant efficacy when tested against pentylentetrazole and AMPA O
NC ONH-n-P r N
2
NH2 26, R1-R2 = -OC H 2O-; S YM 2206 27, R1 = H, R 2 = OM e; S YM 2189
Fig. (9). Phthalazine derivatives.
29) structurally related to 2,3-benzodiazepin-4-one derivatives have been also developed, and the most interesting compound (29) of this series showed potent anticonvulsant efficacy [60]. By analogy with findings for 2,3-benzodiazepine, a five-membered heterocyclic nucleus was also introduced on the phthalazine skeleton; some mono methoxy-substituted analogues proved to be AMPA receptor antagonists [35], while methylenedioxyphthalazines did not show any effect of AMPA antagonism.
R1O
NR 2
R2O
N
NH 2 28, R 1 = R 2 = Me, R 3 = H29, R1-R2 = -CH 2-, R3 = C ONH-nBu
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induced seizures (4.0 mg/kg sc) [65,67]. Compound CP526,427 (31) was also radiolabeled in order to elucidate the inhibitory binding site of allosteric modulators [68]. The different potency of this class of compounds was explained on the basis of a pharmacophore model which consisted of three features: (1) the quinazolin-4-one ring, with a small C-6 substituent, (2) the orthogonal N-3 phenyl ring containing a single ortho substituent, and (3) the aryl ring attached to C-2 through a two-atom spacer. This last feature was identified as the linking unit that could greatly influence the AMPAR antagonism potency [63]. Recently important new classes of non-competitive AMPA receptor antagonists containing different heterocyclic skeleton have been identified. The 2-[N-(4-chlorophenyl)-N-methylamino]-4H-pyrido[3,2-e]-1,3-thiazin-4-one (32, YM928) exerts significant anticonvulsant effects in various seizures models (e.g. MES, ED50 = 4.0-7.4 mg/kg p.o. both in mice and rats), it is orally active and doesn’t induce tolerance after subchronic administration [69,70]. Moreover, compound 32 demonstrated to prevent audiogenic seizures in DBA/2 mice after oral administration at 3mg/kg. Another compound, irampanel (33, BIIR 561CL, dimethyl-[2-[2-(3-phenyl-[1,2,4]oxadiazol-5-yl)-phenoxyl]ethyl]amine hydrochloride) showed anticonvulsant effect; its mechanism is due to the combination of antagonistic action at AMPA receptors and Na+ channel blocking properties [71]. Cl O F
N O N
Me N
R
N
S
32, YM928
MeO Me
N Me
MeO
Ac
O
N O Cl 33, Irampanel
Table 4.
Anticonvulsant Efficacy Against MES Test.
cpd
ED50(mg/kg, po)
GYKI 52466
37.4
GYKI 53733
8.6
GYKI 47621
24.0
21
9.3
Finally, comprehensive quantitative structure-activity relationship (QSAR) studies on an extensive set of negative allosteric modulators have also been reported, in the hope of gaining further insight into the structural requirements for the optimal anticonvulsant effect [78]. A highly predictive QSAR model was thus obtained, revealing high correlation between some electrotopological descriptors and anticonvulsant activity. 5. PHARMACOLOGICAL ACTIVITY OF AMPA RECEPTOR ANTAGONISTS AGAINST EPILEPSY
N Me
30, R1 = CH 2NEt2 , R2 = H; CP-465,022 31, R1 = H, R 2 = CN; C P-526,427
N
The three-dimensional pharmacophore model included two hydrophobic, one hydrogen-bond acceptor and one aromatic features which were considered to be important in obtaining potent AMPAR non-competitive antagonist activity [77]. The most interesting molecule of this series of compounds was 34 (Figure 10) which proved to be in vivo and in vitro more potent than other known AMPA antagonists such as GYKI 52466, CFM-2 and talampanel [74].
1
R2
N
The rational design of new N-acetyl-1-aryl-6,7dimethoxy-1,2,3,4-tetrahydroisoquinoline derivatives as potent anticonvulsant agents [74-76] was suggested by studies of pharmacophore analysis. [74]
34
Fig. (10). Different non-competitive AMPA receptor antagonists
Irampanel suppressed tonic seizures in a maximal electroshock model in mice with an ED50 value of 2.8 mg/kg after subcutaneous administration and protected mice against AMPA-induced toxicity with an ED50 value of 4.5 mg/kg following subcutaneous administration. Despite its interesting anticonvulsant effects, by October 1999 the development was only ongoing for stroke [72]; the neuroprotection provided by this molecule is comparable to the effects of NBQX [73].
It has been shown that AMPA receptor antagonists may be effective for symptomatic treatment of epileptic seizures and in preventing permanent brain damage resulting from prolonged seizure activity. Both competitive and noncompetitive antagonists proved to block seizure activity induced by MES and chemical convulsants in many animal models of epilepsy [38,48,50,52,53,79-95]. Nevertheless, a potential problem associated with the use of AMPAR antagonists as anticonvulsants is that the therapeutic dose for protection against MES-induced seizures is very close to the toxic dose, giving rise to motor impairments [83,84,93]. Furthermore some compounds (e.g. NBQX) are ineffective in blocking seizure activity caused by some convulsants [92]. Anyway some reports found a synergism between NBQX and other anticonvulsants in the MES test [96] or against kindling-induced seizures [83,84,97,98], and this may help to reduce the level of these adverse effects. It has to be noted that the therapeutic margin is wider when these compounds are tested in other models of epilepsy [3,44,46-50,52,53,56,57,60,61,74-76,80,99,100]; however, the relevance of these models for the development of clinically effective anticonvulsants has to be better clarified.
AMPA Receptor Antagonists as Potential Anticonvulsant Drugs
Table 5.
Current Topics in Medicinal Chemistry, 2005, Vol. 5, No. 1
37
Anticonvulsant Effects in Different Seizure Models.
ED50 (µmol/kg, ip) cpd Audiogenic seizures
AMPA-induced seizures
MES
PTZ
GYKI 52466
35.8
40.5
35.7
68.3
GYKI 53733
13.4
29.1
28.8
56.3
22
15.0
25.0
15.9
22.6
23
21.8
37.9
32.1
71.8
25
3.65
17.7
5.93
13.8
29
3.25
47.4
33.1
41.9
34
4.20
7.90
5.17
9.2
The effects of AMPA receptor antagonists against various model of kindling have been reported in literature and it has been observed that the pentylenetetrazole induced kindling is more sensible to antiseizure effects of AMPA antagonists than kindling induced by electrical stimulation of limbic seizures [3,50,81,83,84,86]. Furthermore, different effects of AMPA receptor antagonists against some models of absence epilepsy have been reported: CNQX and NBQX seem to be effective [101] whereas more selective non-competitive AMPAR antagonists (LY 300164 and GYKI 52466) do not significantly change the frequency and the total number of absence epileptic discharges [102,103]. Furthermore, LY 300164 was able to exert additive effects on the antiabsence activity of CGP 36742, a GABAB receptor antagonist, in WAG/Rij genetic model of absence epilepsy [102]. The short duration of action of currently available AMPA receptor antagonists is a further problem for prophylactic use. In addition, sclerosis in the hippocampus and other limbic areas is a common pathological finding in brains from patients with temporal lobe epilepsy (TLE) or partial complex seizures [104-108]. While controversy rages over whether this is a cause or a result of seizure activity [104,109], it is clear from animal models that prolonged seizure activity causes neuronal loss [105,108]. AMPAR antagonists might provide a symptomatic treatment against epileptic seizure activity and, in addition, may be effective in preventing permanent brain damage resulting from prolonged seizure activity. However, the neuronal damage produced by prolonged periods of seizures, such as that caused by kainate and AMPA, is poorly prevented by competitive AMPAR antagonist NBQX [110-112] whereas NMDA receptor antagonists provide substantial protection [113]. Nevertheless, NBQX (20 to 40 mg/kg) has been reported to protect against the brain damage induced by electrically-induced seizures [114].
6. ROLE OF AMPA RECEPTOR ANTAGONISTS IN EPILEPSY Excessive glutamatergic neurotransmission is understood to be one of the primary metabolic and pathological mechanisms behind the aetiology of numerous types of epilepsy [115]. A number of early studies showed that glutamate and kainate were capable of inducing epilepsy in animals that correlated with human symptoms [105]. Since then, a number of functional changes in excitatory amino acid neurotransmission have been reported in seizure-susceptible animals including increased excitatory amino acid-induced Ca2+ influx, altered excitatory amino acid binding, enhanced glutamate and aspartate release, and modulation of glutamate transporter expression and function [6]. Because AMPAR ligands are relatively novel anticonvulsant agents compared for example to benzodiazepines or Na+ channel inhibitors, the potential of AMPA receptor antagonists to attenuate epileptic seizures has not yet been fully investigated. At present, talampanel is the only AMPA receptor antagonist in phase II clinical trial use for the amelioration of epileptic seizures. Interest in iGluR antagonists as potential antiepileptic drugs increased with the discovery of competitive and noncompetitive NMDA receptor antagonists, such as D-CPPene, (E)-4-(3-phosphonopropyl)piperazine-2-carboxylic acid and MK-801, (5S,10R)-(+)-5-methyl-10,11-dihydro5H-dibenzo [a,d]cyclohepten-5,10-imine maleate, and the noncompetitive AMPA receptor antagonist GYKI 52466. All NMDA receptor antagonists showed therapeutic potential in animal models of epilepsy [80,85] but they failed early clinical trials. Ionotropic glutamate AMPA receptor antagonists continue, however, to be investigated as possible therapeutic agents and to further understand the role of glutamate in the aetiology of epilepsy. It is known that AMPA receptors are expressed in the key epileptogenic regions of the brain including the cerebral cortex, the thalamus, the amygdala, the hippocampus, and even the basal ganglia which receives inputs from these regions [116,117].
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7. COMMENTS The focus of this review was to describe competitive and non-competitive AMPAR antagonists able to prevent and/or block the epileptic seizures in different animal models. The possible therapeutic efficacy in epilepsy of AMPA receptor antagonists in animal models of generalized seizures (including clonic, clonic-tonic) and temporal lobe epilepsy (such as those induced by kainate or kindling) suggest a possible role against partial and generalized seizures. No clear effect has been observed against absence seizures. Further studies are requested in order to better characterize the efficacy and safety of AMPAR antagonists, as possible anticonvulsants in animal models of genetic epilepsy, other than GEPRs, WAG/Rij and DBA/2 mice. However, more experimental studies are necessary in order to compare the several AMPAR antagonists in preclinical animal models. Many compounds were synthesized but only a few were adequately screened against models different from those of generalized seizures and partial epilepsy; this approach could better indicate a possible clinical use. Furthermore, in the DBA/2 mouse model of primary generalized seizures some AMPA receptor ligands show equal or greater potency than clinical antiepileptic drugs when administered intraperitoneally. Another important consideration when assessing the therapeutic potential of AMPA receptor ligands is to establish the therapeutic index of such ligands, i.e. the anticonvulsant potency of the ligand compared to its ataxic or sedative potency. Current clinical antiepileptic drugs such as diazepam, carbamazepine, lamotrigine, and sodium valproate exhibit therapeutic indexes of approximately 41, 15, 23, and 7 in DBA/2 mice, respectively. Similarly, some AMPAR antagonists demonstrate a 2-6-fold therapeutic index in the same assay. Other considerations towards evaluating the therapeutic potential of AMPAR antagonists as antiepileptic drugs include drug interactions, absorption with food, metabolism, and protein binding which are yet to be investigated. Preclinical studies positively support the therapeutic potential of AMPAR antagonists in epilepsy and more data are required concerning the efficacy of subtype specific agents in different epilepsy models. Pharmacological data are conspicuously lacking in animal models of epileptogenesis. Prolonged epileptic seizures produce a similar histopathological pattern to that of ischaemic damage. Some studies have investigated the correlation of the antiepileptic effect of AMPAR antagonists with neuroprotection. It is possible that neuroprotective effects may be associated with administration of antiepileptic doses of AMPAR antagonists and therefore add to the therapeutic potential of this class of drugs. Another important consideration regarding the therapeutic relevancy of AMPA receptor antagonists arose from the studies [76,118] where action on multiple targets involved in glutamatergic neurotransmission was found to be more efficacious than action on only one target. Testing with the recent1y developed AMPA receptor antagonists may provide even more opportunity for obtaining the maximum
Chimirri et al.
therapeutic value. It could be interesting to observe which combination of glutamate ligands produces the best therapeutic value according to the animal model of seizures. Whereas selective inactivation of AMPA receptors can provide information of the therapeutic contribution of each receptor subtype alone and help to map epileptic circuitry in the brain, ultimately, antiepileptic drugs directed at the glutamatergic system are likely to be most beneficial when they involve a combination of agents including AMPA receptor modulators. ABBREVATIONS AEDs
=
antiepileptic drugs
AMP397A
=
{[(7-nitro-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-5-ylmethyl)-amino]-methyl}phosphonic acid
AMPA
=
α -amino-3-hydroxy-5-methyl-4isoxazolepropionic acid
AMPAR
=
α -amino-3-hydroxy-5-methyl-4isoxazolepropionic acid receptor
ATPO
=
(S)-2-Amino-3-[5-tert-butyl-3(phosphonomethoxy)-4-isoxazolyl] propionic acid
BIIR 561CL, Irampanel
=
dimethyl-[2-[2-(3-phenyl[1,2,4]oxadiazol-5-yl)-phenoxyl]ethyl]amine hydrochloride
CGP36742 CNQX CP-465,022
= = =
CP-526,427
=
(3-Aminopropyl)butylphosphinic acid 6-cyano-7-nitroquinoxaline-2,3-dione (+)-(aS)-(2-chlorophenyl)-2-[(E)-2-[6(diethylaminomethyl)pyridin-2-yl]vinyl]-6-fluoroquinazolin-4(3H)-one 3-Pyridinecarbonitrile, 2-[2-[3-(2chlorophenyl-4-t)-6-fluoro-3,4-dihydro4-oxo-2-quinazolinyl]ethenyl]- (9CI)
D-CPPene
=
(E)-4-(3-phosphonopropyl)piperazine-2carboxylic acid
DNQX iGluR GABA
= = =
6,7-dinitroquinoxaline-2,3-dione ionotropic glutamate receptor γ-aminobutyric acid
GYKI 47621
=
GYKI 52466
=
6-(4-aminophenyl)-8-chloro-2-methyl11H-imidazo[1,2-c][2,3]benzodiazepine 1-(4-aminophenyl)-4-methyl-7,8methylenedioxy-5H-2,3-benzodiazepine
GYKI 53733, talampanel, LY300164 =
GYKI 53784
=
[(R)-7-acetyl-5-(4-aminophenyl)-8,9dihydro-8-methyl-7H-1,3-dioxolo[4,5h][2,3] benzodiazepine LY303070 [(–)1-(4-aminophenyl)-4methyl-7,8-methylenedioxy-4,5dihydro-3-methylcarbamoyl-2,3benzodiazepine]
AMPA Receptor Antagonists as Potential Anticonvulsant Drugs
Current Topics in Medicinal Chemistry, 2005, Vol. 5, No. 1
KA
=
kainic acid
[5]
LIVBP
=
leucine/ isoleucine/valine binding protein
[6]
MES
=
maximal electroshock
mGluR
=
metabotropic glutamate receptor
MK-801
=
(5S,10R)-(+)-5-methyl-10,11-dihydro5H-dibenzo[a,d]cyclohepten-5,10-imine maleate
[7] [8]
NBQX
=
1,2,3,4-Tetrahydro-6-nitro-2,3-dioxobenzo[f]quinoxaline-7-sulfonamide
NMDA
=
N-methyl-D-aspartic acid
PTZ
=
Pentylentetrazol
QSAR
=
quantitative structure-activity relationship
RPR117824
=
9-carboxymethyl-4-oxo-5H,10Himidazo[1,2-a]indeno[1,2-e]pyrazin-2carboxylic acid
RPR119990
=
9-carboxymethyl-4-oxo-5H,10Himidazo[1,2-a]indeno[1,2-e]pyrazin-2phosphonic acid
S17625
=
6,7-dichloro-2-(1H)-oxoquinoline-3phosphonic acid
SAR
=
structure activity relationship
SYM 2189
=
4-(4-aminophenyl)-1-methyl-6methoxy-N-propyl-1,2dihydrophthalazine-2-carboxamide,
SYM 2206
=
4-(4-aminophenyl)-1-methyl-6,7methylenedioxy-N-propyl-1,2dihydrophthalazine-2-carboxamide,
TLE
=
temporal lobe epilepsy
YM-90K
=
6-(1H-imidazol-1-yl)-7-nitro-2,3(1H,4H)-quinoxalinedione hydrochloride
[9] [10] [11]
[12] [13] [14] [15] [16] [17]
YM-872
=
1(2H)-Quinoxaline acetic acid, 3,4dihydro-7-(1H-imidazol-1-yl)-6-nitro2,3-dioxo
YM-928
=
2-[N-(4-chlorophenyl)-N-methylamino]4H-pyrido[3,2-e]-1,3-thiazin-4-one
[18]
[19] [20] [21] [22]
[23]
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