Epilepsia, 33(Suppl. I):SI-S6, 1992 Raven Press, Ltd., New York 0 International League Against Epilepsy
New Antiepileptic Drugs: From Serendipity to Rational Discovery Roger J. Porter and *Michael A. Rogawski Ofice ofthe Director and *Neuronal Excitability Section, Epilepsy Research Branch, National Institute of Neurological Disorders and Stroke, Bethesda, Maryland, U.S.A.
Summary: Antiepileptic drug discovery has made enormous progress from the serendipity and screening processes of earlier days to the rational drug development of today. The modern era of research began with the recognition that enhancement of inhibitory processes in the brain might favorably influence the propensity for seizures, .y-aminobutyric acid (GABA) being the main inhibitory transmitter. Work in this field led to the development of vigabatrin, which inhibits the enzyme responsible for the degradation of GABA. More recently, research has focused on the therapeutic potential of blocking excitatory amino acids-in particular glu-
tamate. Of the three receptors for glutamate, the N-methylD-aSpartate (NMDA) receptor is considered the one of most interest in epilepsy, and research on a series of competitive NMDA receptor antagonists-especially those that are orally active-is in the forefront of antiepileptic drug development today. A further alternative for diminishing neuronal excitability is to modulate sodium, potassium, or calcium channels. The latter are especially implicated in absence seizures. Key Words: Anticonvulsants-Neurochemistry-Neurotransmitters-GABA-NMDA-Ion channels.
Approximately 50,000,000 persons worldwide have epilepsy, and at least 25% of those afflicted have seizures that are resistant to available medical therapies. Although a number of these refractory patients will be candidates fof surgical intervention, such radical intervention is of limited availability, requiring a specialized team and expensive equipment. Furthermore, only a minority of cases are deemed suitable for surgical therapy. The vast majority of uncontrolled patients, therefore, are at the mercy of the medications available to them. Their sole hope is the eventual development of more effective medications. Although the number of new candidate drugs was very limited only a decade ago, there are now a large number of compounds at various stages of preclinical and clinical development.
used it to treat catamenial seizures. Bromides were the only useful therapy until the development of the barbiturates in the next century. Curiously, bromides still have a limited role for therapy of the disorder, especially in patients who have porphyria-bromide is the only currently marketed antiepileptic drug that does not aggravate the biochemical abnormality in this disease. The drug is relatively toxic, causing dermatitis and psychosis in some patients. Phenobarbital was introduced in 1912 by Hauptmann, who noted its effectiveness and superiority, at least from the standpoint of toxicity, over bromides. Because the barbiturate molecule was easily modified, many analogues of phenobarbital were synthesized; approximately 50 of these were marketed in the United States in the first 35 years of this century. A few of these, such as metharbital and mephobarbital, demonstrated promising antiepileptic activity and continue as marketed drugs (Porter, 1985). The year 1937 marked the beginning of the experimental evaluation of promising anticonvulsant chemicals prior to clinical use. Using a seizure model 6ased on a new electroshock technique for producing con& vulsions in animals (Spiegel, 1937), Memtt and Puttnam (1938a,b) screened a group of compounds sup-
HISTORY OF ANTIEPILEPTIC DRUG DEVELOPMENT
The first drug for that was a contribution to controlling the disorder was potassium bromide; it was intrduced in 1857 by Locock, who Address comespandence and reprint requests to D ~M. . A. R ~ ~ at Bldg. 10, Room 5N244, NINDS, Bethesda, MD 20892, U.S.A.
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R. J. PORTER AND M. A . ROGAWSKI
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plied by Parke-Davis and discovered the anticonvulsant properties of diphenylhydantoin, now called phenytoin. Because phenytoin was well tolerated by laboratory animals, it was subjected to clinical trials in 1938 and marketed that same year. The absence of sedative effects and the dramatic control of seizures observed when phenytoin was added to barbiturate therapy were the key factors in its rapid marketing. In addition, its entry into the market was not delayed by regulatory requirements, because at that time the introduction of new drugs was still regulated by a 1906 statute requiring only that drugs be accurately labeled; proof of their safety or efficacy was not required (Federal Food and Drugs Administration Act, 1906). After 1938, marketing of all drugs in the United States was regulated by the Federal Food, Drugs, and Cosmetic Act, which required proof of safety in addition to the 1906 labeling provisions (Porter, 1990). In 1944, Richards and Everett reported that trimethadione, a potent analgesic compound that was to become the first antiabsence drug, prevented pentylenetetrazol-induced threshold seizures in rodents. They also showed that these seizures were prevented by phenobarbital, but not by phenytoin (Richards and Everett, 1944). Goodman et al. (1953) confirmed these results and showed that phenytoin and phenobarbital modified the pattern of maximal electroshock seizures, but that trimethadione did not. These findings demonstrated the varying anticonvulsant actions of these drugs and the qualitative difference between threshold and maximal seizures (Porter et al., 1984; Porter, 1988). In 1951, Chen et al. investigated the anticonvulsant activity of approximately 65 phenylsuccinimides and found that among the most potent antipentylenetetrazol compounds were phensuximide and methsuximide. Phensuximide was approved for treatment of absence seizures in 1953, and methsuximide in 1957. A third succinimide, ethosuximide, was introduced for the same purpose in 1960 (Porter, 1988). Ethosuximide was the last of the cyclic ureides to be marketed in the United States. From that point on, the development of new drugs concentrated on different molecular structures, resulting in the marketing of carbamazepine, valproate, the benzodiazepines, and, most recently in Europe, vigabatrin, lamotrigine, and oxcarbazepine. MODERN DEVELOPMENT OF ANTIEPILEPTIC DRUGS Enhancement of inhibition The modern era of the search for new antiepileptic drugs began with attempts to develop drugs that facilitate inhibition. The feasibility of this approach is ap-
Epilepsia. Vol. 33, Suppl. I , 1992
parent from the anticonvulsant activity of benzodiazepines and barbiturates, which are well known to potentiate y-aminobutyric acidergic (GABAergic) inhibition (Olsen, 1988; Haefely, 1989). In recent years, a number of other ways of enhancing inhibition have been investigated (see Rogawski and Porter, 1990, for references). The most direct way of enhancing inhibition is with drugs that enter the brain and are converted to either GABA (or structurally related compounds with GABAA receptor agonist activity) or analogues of other endogenous inhibitory substances, such as glycine or taurine. One successful result of the application of this approach is progabide, a lipid-soluble GABA analogue with GABAA receptor agonist activity that, on entry into the brain, is converted to the two additional GABA agonists SL 750 12 and GABAamide, and ultimately to GABA itself. Similarly, milacemide, a glycine prodrug, and taltrimide, an analogue of taurine, have anticonvulsant activity in animal seizure models. An alternative strategy is the inhibition of the GABA catabolic enzyme GABA transaminase (GABAT), which enhances the synaptic availability of GABA by preventing its breakdown to glutamate and succinic semialdehyde. GABA-T inhibitors should theoretically potentiate the action of synaptically released GABA without producing generalized inhibitory effects throughout the brain, as do direct-acting GABA agonists. This latter approach resulted in the development and subsequent marketing of vigabatrin, a GABA-T inhibitor, which is among the most promising of the new antiepileptic drugs. Another strategy for enhancing synaptic GABA levels is blockade of GABA uptake into neurons or glia. Like GABA-T inhibitors, GABA uptake blockers should selectively potentiate the inhibitory effects of synaptically released GABA (Taylor et al., 1990). Conventional blockers of GABA uptake such as nipecotic acid and guavacine have anticonvulsant activity when injected intracerebroventricularly, but these drugs do not penetrate the blood-brain barrier (Croucher et al., 1983). Recently, several lipophilic nipecotic acid derivatives have been described that are active when administered systemically. One of these, C1-966, has a high anticonvulsant potency in animal seizure models but was toxic in human volunteers and was withdrawn from clinical development (Sedman et al., 1990). Another nipecotic acid analogue, tiagabine (Nielsen et al., 1991), may be better tolerated (Mengel et al., 1990) and is currently undergoing clinical trials (M. W. Pierce, personal communication). Diminution of excitation (Fig. 1) A more recent avenue for anticonvulsant drug development is the blockade of synaptic excitation me-
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NEW ANTIEPILEPTIC DRUGS
Recognition site: Polyamine
Glycine
Glutamate
lonophore
lfenprodil
L 687,414
D(-1-CPPene CGS 37849 CGP 39551 CGP 40016 CGP 43487
Dizocilpine ADCI 3-F-PCA PPA
SL 82.0715
Ca2+ Na+ T
EXTRACELLULAR
PPPPP
NMDA Receptor-Channel Complex
INTRACELLULAR
*Required for opening.
K+
FIG. 1. Polyamine, glycine, glutamate (NMDA), and ionophore (ion channel) drug acceptor sites on the NMDA receptor-channel complex, with several representative antagonists acting at each of these sites. Oral activity has been verified for all of the compounds except SL 82.071 5, an analogue of ifenprodil. See the text for references. ADCI, (+)-5-aminocarbonyl-10,11 -dihydro-5H-dibenzo[a,d]cyclohepten5.1 0-imine; 3-F-PCA, 1-(3-fluorophenyl)cyclohexylamine; PPA, 1-phenylcyclopentylamine.
.
diated by N-methyl-D-aspartate (NMDA)-type glutamate receptors. Extensive evidence from in vitro physiological studies supports the concept that NMDA receptors are critical to epileptiform activity and epileptogenesis. Moreover, NMDA antagonists have been shown to exhibit a broad spectrum of anticonvulsant activity in animal seizure models (see Rogawski and Porter, 1990, for references), and are particularly effective against maximal electroshock seizures and alcohol withdrawal seizures (Grant et al., 1990; Morrisett et al., 1990; Liljequist, 1991). The anticonvulsant activity of NMDA antagonists was first established for drugs such as 2-amino-7-phosphonoheptanoic acid (APH) and 2-amino-5-phosphonovaleric acid (APV) (Croucher et al., 1982; Patel et al., 1988) that competitively block the glutamate recognition site of the NMDA receptor-channel complex. Initial problems with limited blood-brain bamer penetrability and poor oral activity of competitive NMDA antagonists have now been overcome with the introduction of several highly effective, orally active competitive antagonists, which are in early-stage clinical trials. These include CGP 37849 (an unsaturated analogue of APV) and its longer-acting carboxyethyl ester CGP 3955 1 (Fagg et al., 1990; Pozza et al., 1990; Schmutz et al., 1990) as well as D-CPPene, an unsaturated derivative of the cyclic APV analogue ~(-)-3-(2-carboxypiperazine-4y1)-propyl- 1-phosphonic acid (Chapman et al., 1990; Patel et al., 1990). Recently, it has been demonstrated
that the biological activity of CGP 37849 and CGP 3955 1 resides in the R enantiomers (CGP 400 16 and CGP 43487, respectively) and it is these compounds that will likely be pursued for further clinical development (Schmutz et al., 199 I). Shortly after the potent anticonvulsant activity of competitive NMDA antagonists was demonstrated, it was recognized that dissociative anesthetics, such as phencyclidine and ketamine, and the dibenzocycloalkenimine dizocilpine (MK-801) also exert their wellknown anticonvulsant activity as a result of an interaction with NMDA receptors (Leander et al., 1988). These compounds bind to a site within the ion channel associated with the NMDA receptor and act to prevent cation flux through the channel (i.e., they are “open channel” or “uncompetitive” antagonists). Although competitive NMDA antagonists have generally been found to cause less neurological impairment (e.g., ataxia) than uncompetitive antagonists at anticonvulsant doses, it has recently been demonstrated that certain low-affinity uncompetitive antagonists may also have relatively favorable toxicity profiles (Rogawski et al., 1989; Blake et al., 1992). Of particular interest in this regard is ADCI, the carboxamide analogue of dizocilpine, which has a therapeutic index comparable to that of carbamazepine (Rogawski et al., 1991). Despite their impressive anticonvulsant activity in animal seizure models and the relatively lower propensity of certain newer compounds to cause neuro-
Epilepsia. Vol: 33. Suppl. 1. 1992
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logical impairment, the utility of NMDA antagonists in epilepsy therapy is uncertain because such compounds may also produce a variety of potentially serious side effects that are not typical of conventional anticonvulsant drugs, including altered sensory processing (e.g., visual illusions) and disruption of learning and memory (Willetts et al., 1991). In addition, both uncompetitive (Olney et al., 1989) and competitive (Olney et al., 1990) NMDA antagonists induce vacuolization in the retrosplenial cortex and cingulate gyrus in rats, and high doses may cause frank neuronal necrosis in these areas (Allen and Iversen, 1991). Areas of vulnerability show early increases in heat shock protein, a putative marker of cell injury (Sharp et al., 1990). Recently, it has been reported that muscarinic cholinergic antagonists and barbiturates can completely protect against the morphological damage caused by both competitive and uncompetitive NMDA antagonists (Olney et al., 1991). Although the mechanism underlying this surprising protective effect is obscure, the observation does suggest that it may be possible to overcome at least one of the potentially serious side effects of NMDA antagonists. There are several other sites on the NMDA receptorchannel complex at which pharmacological antagonists can inhibit NMDA receptor-mediated responses and these could potentially serve as targets for anticonvulsant drugs, including the strychnine-insensitive glycine coagonist site (Thomson, 1990; Huettner, 199 I ) and the polyamine modulatory site (Williams et al., 1991). Although there is evidence that glycine site antagonists have anticonvulsant activity when administered directly into the brain (Singh et al., 1990~; Croucher and Bradford, 199l), such compounds have failed to show significant anticonvulsant activity upon systemic administration, presumably because they fail to penetrate the blood-brain barrier (see also Sheardown et al., 1989). Recently, however, a highly selective, systemically active competitive glycine site antagonist has been described. This compound, an analogue of the glycine site-active enantiomer of HA-966, is an effective anticonvulsant in animal seizure models and has a therapeutic index that is comparable to the newer competitive NMDA recognition site antagonists (M. D. Tricklebank, personal communication). The polyamines spermine and spermidine can potentiate the activity of the NMDA receptor in both radioligand binding (Romano et al., 1991) and electrophysiological (McGurk et al., 1990) test systems, and spermidine can enhance the convulsant action of NMDA in vivo (Singh et al., 19906). Because brain polyamine levels are normally very high, polyamine antagonists should theoretically have anticonvulsant activity. To date, the only polyamine antagonists reEpilepsia. Vol. 33. Suppl. 1. 1992
ported to be capable of permeating the blood-brain barrier are the cerebroprotective drug ifenprodil and its analogue SL 82.07 15 (Carter et al., 1989; Reynolds and Miller, 1989). Both of these have anticonvulsant activity (Pontecorvo et al., 1991; Singh et al., 1991) but preliminary data indicate that the therapeutic index of these compounds may not be substantially better than that of conventional NMDA recognition site antagonists (Perrault et al., 1989). Modulation of Na', K+, and Ca2+channels (Fig. 1) A definitive understanding of the mechanism underlying the anticonvulsant action of phenytoin is not at hand even today, more than half a century after the original description of the drug by Memtt and Putnam. Nevertheless, it is generally accepted that an important action of phenytoin is its use- and voltage-dependent inhibition of the voltage-gated Na' channels that mediate the upstroke of action potentials (Willow and Catterall, 1982; Yaari et al., 1986). There are a large number of anticonvulsant drugs under development that have a spectrum of activity in animal seizure models that is similar to that of phenytoin, including zonisamide, denzimol, nafimidone, ralitoline, topiramate, flunarizine, and remacemide. It is conceivable that these compounds could act on Na+ channels in a way similar to that of phenytoin, although this will need to be verified experimentally. Nevertheless, modulation of the ion channels that mediate the intrinsic excitability of central nervous system (CNS) neurons is clearly a promising strategy for the development of new antiepileptic agents. An alternative approach to diminishing excitability is to stimulate the opening of K+ channels. Activation of K+ channels would be expected either to hyperpolarize neurons and thus inhibit them or to limit action potential firing by increasing the opposing influence that K+ currents normally have on depolarizing Na+ currents. A variety of K+-channel-opening drugs have been described that are active in peripheral tissues. These compounds stimulate the opening of ATPsensitive Kf channels that (except in pancreatic B cells) are quiescent under normal conditions. At least one of these compounds (cromakalim) appears to open ATPsensitive K+ channels in CNS neurons (Politi and Rogawski, 1991) and has anticonvulsant activity both in brain-slice preparations (Alzheimer and ten Bruggencate, 1988)and in animal seizure models when injected intracerebroventricularly (Gandolfo et al., 1989u,b,c). However, K+-channel-opening drugs will remain only of theoretical interest until analogues capable of permeating the blood-brain barrier are developed. Drugs useful in the treatment of generalized tonicclonic and partial seizures, with the notable exception
NEW ANTIEPILEPTIC DRUGS
of valproate, are ineffective against absence seizures, indicating that the pathophysiological mechanisms underlying absence seizures are distinct from those mediating the other seizure types. Recently, it has been proposed that the antiabsence activity of drugs such as ethosuximide and dimethadione (Coulter et al., 1989)-and possibly valproate as well (Kelly et al., 1990)-is a consequence of their ability to inhibit Ttype Ca2+channels in thalamic neurons. This idea is plausible, since T-type Ca2+channels have been shown to mediate the burst firing of thalamic neurons (Suzuki and Rogawski, 1989; Wang et al., 1991).Consequently, a rational approach for the screening of potential antiabsence drugs is to investigate their activity as antagonists of T-type Ca2+channels. As T-type Ca2+channels are probably primed for activation by GABAB receptor-mediated synaptic potentials, an alternative strategy for suppressing thalamic neuron bursting is blockade of GABABreceptors. In fact, there is evidence that GABA-mediated neurotransmission is critical to absence seizures in a rodent model (Liu et al., 1991), and it has been demonstrated that the novel centrally active GABABreceptor antagonist CGP 35348 (Olpe et al., 1990) has antiabsence activity in this model (C. Marescaux and G. Bernasconi, personal communication). As a result of these animal studies, CGP 35348 is being considered for clinical trials in patients with absence seizures. SUMMARY
Antiepileptic drug discovery has evolved from serendipity through random screening to a scientific era where drugs are designed rationally according to modern principals of neuroscience and the art of medicinal chemistry. Of the research directions currently being pursued, the following appear to be particularly promising: enhancement of inhibition, reduction in excitation, and modulation of the ionic channels that are the fundamental mediators of neuronal excitability. The application of modern approaches to drug discovery provides some optimism that effective new compounds will be marketed in the coming decade, with the promise of diminished suffering by persons with uncontrolled epilepsy. REFERENCES Allen HL, lversen LL. Phencyclidine, dizocilpine, and cerebrocortical neurons. Science 1991;247:22 1. AlzheimerC, ten Bmggencate G. Actions of BRL 349 I5 (cromakalim) upon convulsive discharges in guinea pig hippocampal slices. Naunyn Schmiedebergs Arch Pharmacol 1988;337:429-34. Blake PA, Yamaguchi S, Thurkauf A, Rogawski MA. Anticonvulsant I-phenylcycloalkylamines:two analogues with low motor toxicity when orally administered. Epilepsia 1992;33:188-94. Carter C, Rivy JP, Scatton B. Ifenprodil and SL 82.07 15 are antag-
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ylenetetrahydroisoquinoline. J Pharmacol Exp Ther 1989: 2491708- 12. Rogawski MA, Yamaguchi S, Jones SM,Rice KC, Thurkauf A, Monn JA. Anticonvulsant activity of the low affinity uncompetitive NmethylrD-aspartate antagonist (+)-5-aminocarbonyl-l0, 1 l d i hydro-5H-dibenzo[a,d]cyclohepten-5,IO-imine (ADCI): comparison with the structural analogs dizocilpine (MK-801) and carbamazepine. J Pharmacol Exp Ther 199I :259:30-7. Romano C, Williams K, Molinoff PB. Polyamines modulate the binding of ['H]MK-80 I to solubilized N-methyl-D-aspartate receptor. J Neurochem I99 1 ;57:8 I 1-8. Schmutz M, Jeker A, Klebs, K, et al. CGP 401 I6/CGP 43487: competitive N-methyl-D-aspartate receptor antagonists with potent oral anticonvulsant activity [Abstract]. Epilepsia 1991;32(suppl 1):59. Schmutz M. Portet C, Jeker A, et al. The competitive NMDA receptor antagonists CGP 37849 and CGP 3955 I are potent, orally active anticonvulsants in rodents. Nuunyn Schmiedebergs Arch Pharmacol 1990:342:6 1-6. Sedman AJ, Gilmet GP, Sayed AJ, Posvar EL. Initial human safety and tolerance study of a GABA uptake inhibitor, C1-966: potential role of GABA as a mediator in the pathogenesis of schizophrenia and mania. Drug Dev Res 1990:2 1:235-42. Sharp FR, Noble L, Jasper P, Hall J. Heat shock protein HSP72 is induced in cingulate gyrus neurons by MK801 and ketamine [Abstract]. Ann Neurol 1991. Sheardown MJ, Drejer J, Jensen LH, Stidsen CE, Honor6 T. A potent antagonist of the strychnine insensitive glycine receptor has anticonvulsant properties. Eur J Pharmacol 1989;174:197-204. Singh L, Oles RJ, Tricklebank MD. Modulation of seizure susceptibility in the mouse by the strychnine-insensitive glycine recognition site of the NMDA receptor/ion channel complex. Br J Pharmacol 1990a,99:285-8. Singh L, Oles RJ, Vass CA, Woodruff GN. A slow intravenous infusion of N-methyl-DL-aspartateas a seizure model in the mouse. J Neurosci Meth 1991;37:227-32. Singh L. Oles RJ, Woodruff G. In vivo interaction of a polyamine with the NMDA receptor. Eur J Pharmacol 1990b;180:391-2. Spiegel EA. Quantitative determination of the convulsive reactivity by electric stimulation of brain with the skull intact. J Lab Clin Med 1937:22: 1274-6. Suzuki S, Rogawski MA. T-type calcium channels mediate the transition between tonic and phasic firing in thalamic neurons. Proc Natl Acad Sci USA 1989;86:7228-32. Taylor CP, Vartanian MG, Schwarz RD, Rock DM, Callahan MJ, Davis MD. The pharmacology ofC1-966, a potent GABA uptake inhibitor, in vivo and in experimental animals. Drug Dev Res 19902 I: 195-2 15. Thomson AM. Glycine is a coagonist at the NMDA receptor/channel complex. Prog Neurobiol 19903553-74. Wang X-J, Rinzel J, Rogawski MA. A model of the T-type calcium current and the low-threshold spike in thalamic neurons. J Neurophysiol 1991;66:839-50. Willetts J, Balster RL, Leander JD. The behavioral pharmacology of NMDA receptor antagonists. Trends Pharmacol Sci 199I ; 1 I: 423-8. Williams K, Romano C, Dichter MA, Molinoff PB. Modulation of the NMDA receptor by polyamines. L$e Sci 1991:48:469-98. Willow M, Catterall WA. Inhibition ofbinding of ['Hlbatrachotoxinin A 20-alpha-benzoate to sodium channels by the anticonvulsant drugs diphenylhydantoin and carbamazepine. Mol Pharmacol 1982:22:627-35. Yaari Y, Selzer ME, Pincus JH. Phenytoin: mechanisms of its anticonvulsant action. Ann Neurol 1986;20:17 1-84.
New Antiepileptic Drugs: From Serendipity to Rational Discovery Roger J. Porter and *Michael A. Rogawski Ofice ofthe Director and *Neuronal Excitability Section, Epilepsy Research Branch, National Institute of Neurological Disorders and Stroke, Bethesda, Maryland, U.S.A.
Summary: Antiepileptic drug discovery has made enormous progress from the serendipity and screening processes of earlier days to the rational drug development of today. The modern era of research began with the recognition that enhancement of inhibitory processes in the brain might favorably influence the propensity for seizures, .y-aminobutyric acid (GABA) being the main inhibitory transmitter. Work in this field led to the development of vigabatrin, which inhibits the enzyme responsible for the degradation of GABA. More recently, research has focused on the therapeutic potential of blocking excitatory amino acids-in particular glu-
tamate. Of the three receptors for glutamate, the N-methylD-aSpartate (NMDA) receptor is considered the one of most interest in epilepsy, and research on a series of competitive NMDA receptor antagonists-especially those that are orally active-is in the forefront of antiepileptic drug development today. A further alternative for diminishing neuronal excitability is to modulate sodium, potassium, or calcium channels. The latter are especially implicated in absence seizures. Key Words: Anticonvulsants-Neurochemistry-Neurotransmitters-GABA-NMDA-Ion channels.
Approximately 50,000,000 persons worldwide have epilepsy, and at least 25% of those afflicted have seizures that are resistant to available medical therapies. Although a number of these refractory patients will be candidates fof surgical intervention, such radical intervention is of limited availability, requiring a specialized team and expensive equipment. Furthermore, only a minority of cases are deemed suitable for surgical therapy. The vast majority of uncontrolled patients, therefore, are at the mercy of the medications available to them. Their sole hope is the eventual development of more effective medications. Although the number of new candidate drugs was very limited only a decade ago, there are now a large number of compounds at various stages of preclinical and clinical development.
used it to treat catamenial seizures. Bromides were the only useful therapy until the development of the barbiturates in the next century. Curiously, bromides still have a limited role for therapy of the disorder, especially in patients who have porphyria-bromide is the only currently marketed antiepileptic drug that does not aggravate the biochemical abnormality in this disease. The drug is relatively toxic, causing dermatitis and psychosis in some patients. Phenobarbital was introduced in 1912 by Hauptmann, who noted its effectiveness and superiority, at least from the standpoint of toxicity, over bromides. Because the barbiturate molecule was easily modified, many analogues of phenobarbital were synthesized; approximately 50 of these were marketed in the United States in the first 35 years of this century. A few of these, such as metharbital and mephobarbital, demonstrated promising antiepileptic activity and continue as marketed drugs (Porter, 1985). The year 1937 marked the beginning of the experimental evaluation of promising anticonvulsant chemicals prior to clinical use. Using a seizure model 6ased on a new electroshock technique for producing con& vulsions in animals (Spiegel, 1937), Memtt and Puttnam (1938a,b) screened a group of compounds sup-
HISTORY OF ANTIEPILEPTIC DRUG DEVELOPMENT
The first drug for that was a contribution to controlling the disorder was potassium bromide; it was intrduced in 1857 by Locock, who Address comespandence and reprint requests to D ~M. . A. R ~ ~ at Bldg. 10, Room 5N244, NINDS, Bethesda, MD 20892, U.S.A.
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R. J. PORTER AND M. A . ROGAWSKI
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plied by Parke-Davis and discovered the anticonvulsant properties of diphenylhydantoin, now called phenytoin. Because phenytoin was well tolerated by laboratory animals, it was subjected to clinical trials in 1938 and marketed that same year. The absence of sedative effects and the dramatic control of seizures observed when phenytoin was added to barbiturate therapy were the key factors in its rapid marketing. In addition, its entry into the market was not delayed by regulatory requirements, because at that time the introduction of new drugs was still regulated by a 1906 statute requiring only that drugs be accurately labeled; proof of their safety or efficacy was not required (Federal Food and Drugs Administration Act, 1906). After 1938, marketing of all drugs in the United States was regulated by the Federal Food, Drugs, and Cosmetic Act, which required proof of safety in addition to the 1906 labeling provisions (Porter, 1990). In 1944, Richards and Everett reported that trimethadione, a potent analgesic compound that was to become the first antiabsence drug, prevented pentylenetetrazol-induced threshold seizures in rodents. They also showed that these seizures were prevented by phenobarbital, but not by phenytoin (Richards and Everett, 1944). Goodman et al. (1953) confirmed these results and showed that phenytoin and phenobarbital modified the pattern of maximal electroshock seizures, but that trimethadione did not. These findings demonstrated the varying anticonvulsant actions of these drugs and the qualitative difference between threshold and maximal seizures (Porter et al., 1984; Porter, 1988). In 1951, Chen et al. investigated the anticonvulsant activity of approximately 65 phenylsuccinimides and found that among the most potent antipentylenetetrazol compounds were phensuximide and methsuximide. Phensuximide was approved for treatment of absence seizures in 1953, and methsuximide in 1957. A third succinimide, ethosuximide, was introduced for the same purpose in 1960 (Porter, 1988). Ethosuximide was the last of the cyclic ureides to be marketed in the United States. From that point on, the development of new drugs concentrated on different molecular structures, resulting in the marketing of carbamazepine, valproate, the benzodiazepines, and, most recently in Europe, vigabatrin, lamotrigine, and oxcarbazepine. MODERN DEVELOPMENT OF ANTIEPILEPTIC DRUGS Enhancement of inhibition The modern era of the search for new antiepileptic drugs began with attempts to develop drugs that facilitate inhibition. The feasibility of this approach is ap-
Epilepsia. Vol. 33, Suppl. I , 1992
parent from the anticonvulsant activity of benzodiazepines and barbiturates, which are well known to potentiate y-aminobutyric acidergic (GABAergic) inhibition (Olsen, 1988; Haefely, 1989). In recent years, a number of other ways of enhancing inhibition have been investigated (see Rogawski and Porter, 1990, for references). The most direct way of enhancing inhibition is with drugs that enter the brain and are converted to either GABA (or structurally related compounds with GABAA receptor agonist activity) or analogues of other endogenous inhibitory substances, such as glycine or taurine. One successful result of the application of this approach is progabide, a lipid-soluble GABA analogue with GABAA receptor agonist activity that, on entry into the brain, is converted to the two additional GABA agonists SL 750 12 and GABAamide, and ultimately to GABA itself. Similarly, milacemide, a glycine prodrug, and taltrimide, an analogue of taurine, have anticonvulsant activity in animal seizure models. An alternative strategy is the inhibition of the GABA catabolic enzyme GABA transaminase (GABAT), which enhances the synaptic availability of GABA by preventing its breakdown to glutamate and succinic semialdehyde. GABA-T inhibitors should theoretically potentiate the action of synaptically released GABA without producing generalized inhibitory effects throughout the brain, as do direct-acting GABA agonists. This latter approach resulted in the development and subsequent marketing of vigabatrin, a GABA-T inhibitor, which is among the most promising of the new antiepileptic drugs. Another strategy for enhancing synaptic GABA levels is blockade of GABA uptake into neurons or glia. Like GABA-T inhibitors, GABA uptake blockers should selectively potentiate the inhibitory effects of synaptically released GABA (Taylor et al., 1990). Conventional blockers of GABA uptake such as nipecotic acid and guavacine have anticonvulsant activity when injected intracerebroventricularly, but these drugs do not penetrate the blood-brain barrier (Croucher et al., 1983). Recently, several lipophilic nipecotic acid derivatives have been described that are active when administered systemically. One of these, C1-966, has a high anticonvulsant potency in animal seizure models but was toxic in human volunteers and was withdrawn from clinical development (Sedman et al., 1990). Another nipecotic acid analogue, tiagabine (Nielsen et al., 1991), may be better tolerated (Mengel et al., 1990) and is currently undergoing clinical trials (M. W. Pierce, personal communication). Diminution of excitation (Fig. 1) A more recent avenue for anticonvulsant drug development is the blockade of synaptic excitation me-
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NEW ANTIEPILEPTIC DRUGS
Recognition site: Polyamine
Glycine
Glutamate
lonophore
lfenprodil
L 687,414
D(-1-CPPene CGS 37849 CGP 39551 CGP 40016 CGP 43487
Dizocilpine ADCI 3-F-PCA PPA
SL 82.0715
Ca2+ Na+ T
EXTRACELLULAR
PPPPP
NMDA Receptor-Channel Complex
INTRACELLULAR
*Required for opening.
K+
FIG. 1. Polyamine, glycine, glutamate (NMDA), and ionophore (ion channel) drug acceptor sites on the NMDA receptor-channel complex, with several representative antagonists acting at each of these sites. Oral activity has been verified for all of the compounds except SL 82.071 5, an analogue of ifenprodil. See the text for references. ADCI, (+)-5-aminocarbonyl-10,11 -dihydro-5H-dibenzo[a,d]cyclohepten5.1 0-imine; 3-F-PCA, 1-(3-fluorophenyl)cyclohexylamine; PPA, 1-phenylcyclopentylamine.
.
diated by N-methyl-D-aspartate (NMDA)-type glutamate receptors. Extensive evidence from in vitro physiological studies supports the concept that NMDA receptors are critical to epileptiform activity and epileptogenesis. Moreover, NMDA antagonists have been shown to exhibit a broad spectrum of anticonvulsant activity in animal seizure models (see Rogawski and Porter, 1990, for references), and are particularly effective against maximal electroshock seizures and alcohol withdrawal seizures (Grant et al., 1990; Morrisett et al., 1990; Liljequist, 1991). The anticonvulsant activity of NMDA antagonists was first established for drugs such as 2-amino-7-phosphonoheptanoic acid (APH) and 2-amino-5-phosphonovaleric acid (APV) (Croucher et al., 1982; Patel et al., 1988) that competitively block the glutamate recognition site of the NMDA receptor-channel complex. Initial problems with limited blood-brain bamer penetrability and poor oral activity of competitive NMDA antagonists have now been overcome with the introduction of several highly effective, orally active competitive antagonists, which are in early-stage clinical trials. These include CGP 37849 (an unsaturated analogue of APV) and its longer-acting carboxyethyl ester CGP 3955 1 (Fagg et al., 1990; Pozza et al., 1990; Schmutz et al., 1990) as well as D-CPPene, an unsaturated derivative of the cyclic APV analogue ~(-)-3-(2-carboxypiperazine-4y1)-propyl- 1-phosphonic acid (Chapman et al., 1990; Patel et al., 1990). Recently, it has been demonstrated
that the biological activity of CGP 37849 and CGP 3955 1 resides in the R enantiomers (CGP 400 16 and CGP 43487, respectively) and it is these compounds that will likely be pursued for further clinical development (Schmutz et al., 199 I). Shortly after the potent anticonvulsant activity of competitive NMDA antagonists was demonstrated, it was recognized that dissociative anesthetics, such as phencyclidine and ketamine, and the dibenzocycloalkenimine dizocilpine (MK-801) also exert their wellknown anticonvulsant activity as a result of an interaction with NMDA receptors (Leander et al., 1988). These compounds bind to a site within the ion channel associated with the NMDA receptor and act to prevent cation flux through the channel (i.e., they are “open channel” or “uncompetitive” antagonists). Although competitive NMDA antagonists have generally been found to cause less neurological impairment (e.g., ataxia) than uncompetitive antagonists at anticonvulsant doses, it has recently been demonstrated that certain low-affinity uncompetitive antagonists may also have relatively favorable toxicity profiles (Rogawski et al., 1989; Blake et al., 1992). Of particular interest in this regard is ADCI, the carboxamide analogue of dizocilpine, which has a therapeutic index comparable to that of carbamazepine (Rogawski et al., 1991). Despite their impressive anticonvulsant activity in animal seizure models and the relatively lower propensity of certain newer compounds to cause neuro-
Epilepsia. Vol: 33. Suppl. 1. 1992
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logical impairment, the utility of NMDA antagonists in epilepsy therapy is uncertain because such compounds may also produce a variety of potentially serious side effects that are not typical of conventional anticonvulsant drugs, including altered sensory processing (e.g., visual illusions) and disruption of learning and memory (Willetts et al., 1991). In addition, both uncompetitive (Olney et al., 1989) and competitive (Olney et al., 1990) NMDA antagonists induce vacuolization in the retrosplenial cortex and cingulate gyrus in rats, and high doses may cause frank neuronal necrosis in these areas (Allen and Iversen, 1991). Areas of vulnerability show early increases in heat shock protein, a putative marker of cell injury (Sharp et al., 1990). Recently, it has been reported that muscarinic cholinergic antagonists and barbiturates can completely protect against the morphological damage caused by both competitive and uncompetitive NMDA antagonists (Olney et al., 1991). Although the mechanism underlying this surprising protective effect is obscure, the observation does suggest that it may be possible to overcome at least one of the potentially serious side effects of NMDA antagonists. There are several other sites on the NMDA receptorchannel complex at which pharmacological antagonists can inhibit NMDA receptor-mediated responses and these could potentially serve as targets for anticonvulsant drugs, including the strychnine-insensitive glycine coagonist site (Thomson, 1990; Huettner, 199 I ) and the polyamine modulatory site (Williams et al., 1991). Although there is evidence that glycine site antagonists have anticonvulsant activity when administered directly into the brain (Singh et al., 1990~; Croucher and Bradford, 199l), such compounds have failed to show significant anticonvulsant activity upon systemic administration, presumably because they fail to penetrate the blood-brain barrier (see also Sheardown et al., 1989). Recently, however, a highly selective, systemically active competitive glycine site antagonist has been described. This compound, an analogue of the glycine site-active enantiomer of HA-966, is an effective anticonvulsant in animal seizure models and has a therapeutic index that is comparable to the newer competitive NMDA recognition site antagonists (M. D. Tricklebank, personal communication). The polyamines spermine and spermidine can potentiate the activity of the NMDA receptor in both radioligand binding (Romano et al., 1991) and electrophysiological (McGurk et al., 1990) test systems, and spermidine can enhance the convulsant action of NMDA in vivo (Singh et al., 19906). Because brain polyamine levels are normally very high, polyamine antagonists should theoretically have anticonvulsant activity. To date, the only polyamine antagonists reEpilepsia. Vol. 33. Suppl. 1. 1992
ported to be capable of permeating the blood-brain barrier are the cerebroprotective drug ifenprodil and its analogue SL 82.07 15 (Carter et al., 1989; Reynolds and Miller, 1989). Both of these have anticonvulsant activity (Pontecorvo et al., 1991; Singh et al., 1991) but preliminary data indicate that the therapeutic index of these compounds may not be substantially better than that of conventional NMDA recognition site antagonists (Perrault et al., 1989). Modulation of Na', K+, and Ca2+channels (Fig. 1) A definitive understanding of the mechanism underlying the anticonvulsant action of phenytoin is not at hand even today, more than half a century after the original description of the drug by Memtt and Putnam. Nevertheless, it is generally accepted that an important action of phenytoin is its use- and voltage-dependent inhibition of the voltage-gated Na' channels that mediate the upstroke of action potentials (Willow and Catterall, 1982; Yaari et al., 1986). There are a large number of anticonvulsant drugs under development that have a spectrum of activity in animal seizure models that is similar to that of phenytoin, including zonisamide, denzimol, nafimidone, ralitoline, topiramate, flunarizine, and remacemide. It is conceivable that these compounds could act on Na+ channels in a way similar to that of phenytoin, although this will need to be verified experimentally. Nevertheless, modulation of the ion channels that mediate the intrinsic excitability of central nervous system (CNS) neurons is clearly a promising strategy for the development of new antiepileptic agents. An alternative approach to diminishing excitability is to stimulate the opening of K+ channels. Activation of K+ channels would be expected either to hyperpolarize neurons and thus inhibit them or to limit action potential firing by increasing the opposing influence that K+ currents normally have on depolarizing Na+ currents. A variety of K+-channel-opening drugs have been described that are active in peripheral tissues. These compounds stimulate the opening of ATPsensitive Kf channels that (except in pancreatic B cells) are quiescent under normal conditions. At least one of these compounds (cromakalim) appears to open ATPsensitive K+ channels in CNS neurons (Politi and Rogawski, 1991) and has anticonvulsant activity both in brain-slice preparations (Alzheimer and ten Bruggencate, 1988)and in animal seizure models when injected intracerebroventricularly (Gandolfo et al., 1989u,b,c). However, K+-channel-opening drugs will remain only of theoretical interest until analogues capable of permeating the blood-brain barrier are developed. Drugs useful in the treatment of generalized tonicclonic and partial seizures, with the notable exception
NEW ANTIEPILEPTIC DRUGS
of valproate, are ineffective against absence seizures, indicating that the pathophysiological mechanisms underlying absence seizures are distinct from those mediating the other seizure types. Recently, it has been proposed that the antiabsence activity of drugs such as ethosuximide and dimethadione (Coulter et al., 1989)-and possibly valproate as well (Kelly et al., 1990)-is a consequence of their ability to inhibit Ttype Ca2+channels in thalamic neurons. This idea is plausible, since T-type Ca2+channels have been shown to mediate the burst firing of thalamic neurons (Suzuki and Rogawski, 1989; Wang et al., 1991).Consequently, a rational approach for the screening of potential antiabsence drugs is to investigate their activity as antagonists of T-type Ca2+channels. As T-type Ca2+channels are probably primed for activation by GABAB receptor-mediated synaptic potentials, an alternative strategy for suppressing thalamic neuron bursting is blockade of GABABreceptors. In fact, there is evidence that GABA-mediated neurotransmission is critical to absence seizures in a rodent model (Liu et al., 1991), and it has been demonstrated that the novel centrally active GABABreceptor antagonist CGP 35348 (Olpe et al., 1990) has antiabsence activity in this model (C. Marescaux and G. Bernasconi, personal communication). As a result of these animal studies, CGP 35348 is being considered for clinical trials in patients with absence seizures. SUMMARY
Antiepileptic drug discovery has evolved from serendipity through random screening to a scientific era where drugs are designed rationally according to modern principals of neuroscience and the art of medicinal chemistry. Of the research directions currently being pursued, the following appear to be particularly promising: enhancement of inhibition, reduction in excitation, and modulation of the ionic channels that are the fundamental mediators of neuronal excitability. The application of modern approaches to drug discovery provides some optimism that effective new compounds will be marketed in the coming decade, with the promise of diminished suffering by persons with uncontrolled epilepsy. REFERENCES Allen HL, lversen LL. Phencyclidine, dizocilpine, and cerebrocortical neurons. Science 1991;247:22 1. AlzheimerC, ten Bmggencate G. Actions of BRL 349 I5 (cromakalim) upon convulsive discharges in guinea pig hippocampal slices. Naunyn Schmiedebergs Arch Pharmacol 1988;337:429-34. Blake PA, Yamaguchi S, Thurkauf A, Rogawski MA. Anticonvulsant I-phenylcycloalkylamines:two analogues with low motor toxicity when orally administered. Epilepsia 1992;33:188-94. Carter C, Rivy JP, Scatton B. Ifenprodil and SL 82.07 15 are antag-
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onists at the polyamine site of the N-methyl-Daspartate (NMDA) receptor. Eur J Pharmacol 1989;164:6 1 1-2. Chapman AG, Graham J, Meldrum BS. Potent oral anticonvulsant action of CPP and CPPene in DBA/2 mice. Eur J Pharmacol 1990;178:97-9. Chen G, Portman R, Ensor CR, Bratton AC Jr. The anticonvulsant activity of alpha-phenyl succinimides. J Pharmacol Exp Ther I95 I ;10354-6 I . Coulter DA, Huguenard JR, Prince DA. Characterization of ethosuximide reduction of low-threshold calcium current in thalamic neurons. Ann Neurol 1989;25:582-93. Croucher MJ, Bradford HF. The influence of strychnine-insensitive glycine receptor agonists and antagonists on generalized seizure thresholds. Brain Res 199 1;543:9 1-6. Croucher MJ, Collins JF, Meldrum BS. Anticonvulsant action of excitatory amino antagonists. Science 1982;216:899-90 I . Croucher MJ, Meldrum BS, Krogsgaard-Larsen P. Anticonvulsant activity of GABA uptake inhibitors and their prodrugs following central or systemic administration. Eur J Pharmacol I983;89: 2 17-28. F a g GE, Olpe H-R, Pozza MF, et al. CGP 37849 and CGP 3955 I: novel and potent competitive N-methyl-Daspartate receptor antagonists with oral activity. Br J Pharmacol 1990;99:79 1-7. Gandolfo G, Gottesmann C, Bidard J-N, Lazdunski M. K+ channel openers prevent epilepsy induced by the bee venom peptide MCD. Eur J Pharmacol 1989a;159:329-30. Gandolfo G, Gottesmann C, Bidard J-N, Lazdunski M. Subtypes of I(+channels differentiated by the effect of K+ channel openers upon K+ channel blocker-induced seizures. Brain Res I9896;495: 169-92. Gandolfo G, Romettino S, Gottesmann C, et al. K+ channel openers decrease seizures in genetically epileptic rats. Eur J Pharmacol 1989~167: I8 1-3. Goodman LS, Grewal MS. Brown WC, Swinyard EA. Comparison of maximal seizures evoked by pentylenetetrazol (Metrazol) and electroshock in mice, and their modification by anticonvulsants. JPharmaeol Exp Ther 1953;108:168-76. Grant KA, Valverius P, Hudspith M, Tabakoff B. Ethanol withdrawal seizures and the NDMA receptor complex. Eur J Pharmacol 1990;I76:289-96. Haefely W. Benzodiazepines: mechanisms of action. In: Levy R, Mattson R, Meldrum B, Penry JK, Dreifuss FE, eds. Anliepilepfic drugs, 3rd edition. New York: Raven Press, 1989:721-34. Huettner JE. Competitive antagonism of glycine at the N-methylD-aspartate (NMDA) receptor. Biochem Pharmacol 1991;4 1:916. Kelly KM, Gross RA, MacDonald RL. Valproic acid selectively reduces the low-threshold (T) calcium current in rat nodose neurons. Neurosci Lett 1990;I 16:233-8. Leander JD, Rathbun RC, Zimmerman DM. Anticonvulsant effects of phencyclidine-like drugs: relation to N-methyl-D-aspartic acid antagonism. Bruin Res 1988;454:368-72. Liljequist S. The competitive NMDA receptor antagonist, CGP 3955 1 , inhibits ethanol withdrawal seizures. Eur J Pharmacol 1991;192:197-8. Liu Z, Vergnes M, Depaulis A, Marescaux C. Evidence for a critical role of GABAergictransmission within the thalamus in the genesis and control of absence seizures in the rat. Brain Res 1991;545: 1-7. McGurk JF, Bennett MV, Zukin RS. Polyamines potentiate responses of N-methyl-Daspartate receptors expressed in Xenopus oocytes. Proc Natl Acad Sci USA 1990;87:9971-4. Mengel HB, Mant TGK, McKelvy JM, Pierce MW. Tiagabine. Phase 1study of safety and tolerance followingsingle oral doses. Epilepsia 1990;31:642. Memtt HH, Putnam TJ. A new series ofanticonvulsant drugs tested by experiments on animals. Arch Neurol Psychiatry 1938a;39: 1003- 15. Merritt HH, Putnam TJ. Sodium diphenylhydantoinate in the treatment of convulsive disorders. JAMA 1938b;l I 1: 1068-73. Momsett RA, Rezvani AH, Overstreet D, Janowsky DS, Wilson WA,
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