Fig. 2. Antagonists of the ion channel of the NMDA protect against anticonvulsant-resistant convulsant effects of cocaine in mice (A) but produce behavioral side effects at comparable doses (B). (From ref. 13 with permission of the publisher.)

disrupting doses (29). In addition, there is general agreement that low-affinity channel-blocking NMDA-receptor antagonists like ADCI do not replicate the discriminative stimulus effects of dizocilpine or PCP (18). However, some of these agents, notably memantine, may, in some cases, substitute (18,29,30). In another model predictive of PCP-like side effects (14), memantine produced ataxia like that of high-affinity ligands but did not produce locomotor stimulation typical of dissociative anestheticlike agents (29). Memantine has been used in Europe for the treatment of dementia, Parkinson's disease, drug-induced extrapyramidal syndromes, neuroleptic malignant syndrome, and spasticity (2,31). Although side effects have been reported (32-34), memantine appears to carry a far lower risk of inducing psychotomimetic symptoms and neurological impairment than high-affinity

Fig. 3. Affinities of uncompetitive NMDA receptor antagonists for the NMDA receptor ion channel correlate with their potencies to protect against cocaine-induced convulsions (A) and to produce behavioral side effects as measured by the inverted screen test (B). (From ref. 13, with permission from the publisher.)

Fig. 3. Affinities of uncompetitive NMDA receptor antagonists for the NMDA receptor ion channel correlate with their potencies to protect against cocaine-induced convulsions (A) and to produce behavioral side effects as measured by the inverted screen test (B). (From ref. 13, with permission from the publisher.)

antagonists (2). The drug is currently under development for the treatment of neuropathic pain and AIDS dementia. Preclinical and clinical data suggest that amantadine may have similar therapeutic activities (2,31). However, amantadine has very weak activity as an NMDA-receptor antagonist in vitro and does not protect against NMDA-induced convulsions in vivo (29). Whether it acts as a low-affinity NMDA-receptor antagonist at clinically relevant doses is uncertain. NPS 1506 is a moderate-affinity uncompetitive NMDA-receptor antagonist with neuroprotective activity in rodent models of

Fig. 4. High-affinity NMDA receptor antagonists of the ion channel produce both a unique combination of sedativelike and stimulantlike behavioral effects in mice. (From ref. 14, with permission from the publisher.)

stroke and head trauma (35). Early clinical trials have revealed good tolerability at doses in excess of those that confer neuroprotection in rodents.

The basis for the improved toxicity profiles of low-affinity channel-blocking NMDA antagonists is not fully understood, but may relate to a variety of factors, including faster blocking kinetics, partial trapping, reduced agonist-independent (closed-channel) block, subunit selectivity (leading to regional differences in action), and combined block at allosteric sites on the NMDA-receptor complex apart from the channel-blocking site (8,36,37). In addition, the low affinity of these compounds for the

Some Competitive NMDA Receptor Antagonists


Clinical status

Selfotel (CGS 19755) D-CPP-ene (SDZ EAA-494) MDL 100,453 NPC 17742

Prior development—stroke In development—traumatic brain injury In development—epilepsy, stroke Preclinical—stroke

(+)-CPP CGP 37849 NPC 12626 LY 274614 LY 235959 LY 233536

NMDA-receptor-associated ion channel also makes the possibility that they will have promiscuous actions at sites other than NMDA receptors (8,38). For example, felbamate, in addition to its actions on NMDA receptors, is also a low-efficacy positive allosteric modulator of GABA receptors (39) and remacemide, its active des-glycine metabolite ARL 12495AA, and ADCI all act as state-dependent blockers of voltage-activated Na+ channels (see ref. 8). Such actions on multiple receptor targets may produce additive or synergistic therapeutic activities, but toxicities at each target may be distinct and nonadditive, resulting in superior therapeutic activity and reduced toxicity in comparison with agents that target NMDA receptors alone.

A body of preclinical (see ref. 40; subsequent chapters of this book) and clinical (cf. ref. 41) evidence attests to the potential therapeutic utility of ibogaine for the treatment of drug dependence. Although this compound has multiple pharmacological actions, ibogaine is well recognised as a low-affinity channel blocker of the NMDA receptor, an effect that may, at least in part, be responsible for its antiaddictive activity (40,42,43). Ibogaine produces striking behavioral disruptions at doses claimed to be effective in drug-dependence treatment, and at high doses, it produces hallucinations. In addition, the drug exhibits PCP-like subjective effects as determined in drug discrimination experiments (42). Analogs of ibogaine and of ibogamine have recently been patented with claims of antiad-dictive efficacy in rats (see ref. 44).

2.2. Competitive NMDA Recognition-Site Antagonists

Competitive NMDA-receptor antagonists inhibit activation of NMDA receptors by occupying the glutamate recognition site of the receptor-channel complex and preventing binding of the neurotransmitter glutamate (see Fig. 1). Like uncompetitive antagonists, competitive NMDA-receptor antagonists have a diversity of potential clinical applications, including the treatment of drug dependence (see subsequent chapters of this book). A large, structurally diverse group of glutamate recognition-site antagonists is now available with good bioavailability and favorable pharmacokinetic properties (Table 2). Many of these agents have long-lasting activity after oral administration (e.g., CGS 19755, D-CPPene, CGP 37849, LY 274614).

Although studies in animals suggested that competitive NMDA recognition-site antagonists would have reduced liability for producing dissociative anestheticlike motor and subjective side effects (see refs. 2,3, 45, and 46), neurobehavioral toxicities have occurred in humans that were not fully anticipated. For example, in clinical trials for stroke and traumatic head injury, D-CPPene and CGS 19755 demonstrated side effects reminiscent of those observed with dizocilpine and PCP (cf. refs. 2,47, and 48). Indeed, competitive antagonists can produce prominent dissociative anestheticlike motor disturbances such as head weaving, body rolling, hyperlocomotion, and ataxia in rodents (15). Moreover,

Carter (49) observed a positive correlation between the potencies of both competitive and uncompetitive NMDA-receptor antagonists for inducing motor incoordination in the rotorod test and their potencies to inhibit NMDA-induced lethality (an in vivo measure of NMDA-receptor blockade). At high doses, the competitive antagonists CGS 19755, NPC 17742, (±)-CPP, and LY 233536 all produced full or nearly full substitution for the discriminative stimulus effects of dizocilpine in mice (19). Although competitive antagonists may not have the same propensity for producing certain behavioral side effects such as stereotypies and disturbances of locomotion that are common with uncompetitive NMDA antagonists, these effects do occur and may be especially prominent in sensitized states such as in amygdaloid kindled animals (50,51). Furthermore, as is the case with uncompetitive antagonists, competitive antagonists can also produce neuronal vacuolization and morphological damage in certain brain regions (22). Tolerance does not seem to develop to either the therapeutic activity or the side effects (52). On the whole, the preclinical and clinical data have led many investigators to lose enthusiasm for the clinical potential of competitive antagonists.

Despite the potential drawbacks of this class of agents, selected competitive antagonists may have reduced liability for side effects in comparison with other members of the class. For example, although the protective indicies (ratio of TD50 value for induction of toxicity and ED50 for seizure protection) of many competitive antagonists is near 1 when tested in mice against cocaine-induced convulsions (13), at least one competitive blocker, LY 233536, has a protective index as high as 7. This compound has previously been reported to display a less debilitating behavioral profile than that of other competitive antagonists (14). On the other hand, the competitive antagonist LY 274614 and its active isomer, LY 235959, produced profound and potent suppression of behavior (14,19,53). The lack of substitution of these latter two compounds in mice trained to discriminate dizocilpine from saline may have been due to these behavioral effects that made it impossible to test higher doses. The recognition that there can be large differences in the behavioral toxicities of competitive NMDA recognition-site antagonists suggests that it may be premature to conclude that this class of agent is not clinically viable.

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