NR2BSelective Ligands

NMDA receptors in mammalian neurons are believed to be heterooligomers formed by the coassembly of an obligatory NR1 subunit and at least one type of NR2 subunit (see Chapter 1). Four NR2 subunits have been identified, each of which exhibits a distinct regional distribution and developmental expression pattern. The four distinct NR2 subunits confer unique pharmacological and biophysical properties upon the NMDA receptors from which they are assembled. In addition, the NR1 subunit exists in multiple alternatively spliced forms that can provide further diversity to NMDA receptors. Selective targeting of specific NMDA-receptor subtypes is a reasonable approach for the development of NMDA-receptor antagonists with improved therapeutic activity and reduced toxicity. Many antagonists show small potency differences at NMDA receptors composed of different subunits. For example, the competitive NMDA recognition-site antagonist (±)-CPP appears to have modestly higher affinity for NMDA receptors composed of a form of the NR1 subunit containing an insert generated by the inclusion of 21 amino acids coded by the alternatively spliced exon 5 (see refs. 2 and 73). To date, however, the only NMDA-receptor isoforms that can be targeted in a therapeutically relevant way are those containing the NR2B subunit (Fig. 1). NR2B selectivity was first described for the phenylethylamine ifenprodil, and, subsequently, the related compounds eliprodil, CP101,606, Ro 25-6981, and nylidrin were found to have similar selectivity (74-77). (see Table 4) and actions governed by their ability to regulate proton inhibition (cf. ref. 78). Despite their relatively potent NMDA-receptor-blocking activity, ifenprodil and eliprodil generally display more favorable toxicity profiles than other NMDA receptor antagonists (79). At neuroprotective doses, they do not produce neurological impairment, do not substitute for PCP in drug-discrimination studies, nor do they induce amnestic effects in passive avoidance testing (2,3). In addition, ifenprodil and eliprodil block cocaine-induced seizures at doses that do not produce failures in the inverted screen test (13). Moreover, clinical trials have indicated that these compounds do not produce psychostimulant, amnesic, or psychotomimetic effects in humans. Finally, eliprodil does not appear to produce the pathomorphological changes that have been observed with other NMDA receptor antagonists (80). These NR2B-selective antagonists may also have additive or synergistic effects when given in conjunction with other NMDA-receptor antagonists (cf. ref. 81).

The anticonvulsants felbamate and ADCI also exhibit moderate NR2B selectivity and this may in part account for their favorable neurobehavioral tolerability in comparison with other NMDA-receptor antagonists (18,82,83). Conantokin G, a component of a cone snail toxin that is currently in development as an anticonvulsant, appears to act as a competitive NMDA recognition-site antagonist with selectivity for the NR2B subunit (84). The butyrophenones haloperidol, droperidol, and spiperone also exhibit NR2B-selective antagonist activity, but this is not of practical utility in behavioral studies because these compounds have a diversity of other pharmacological actions, the most prominent of which is dopamine receptor blockade (75,85,86).

Although the basis for the improved neurobehavioral toxicity of NR2B-selective NMDA-receptor antagonists is not well understood, it could relate to the more restricted distribution of NR2B-contain-ing NMDA receptors. Thus, unlike the NR2A subunit that is distributed ubiquitously in the central nervous system, expression of the NR2B subunit in adults is largely restricted to the forebrain (87).

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