In development—stroke In development—stoke, head injury In development—stroke, pain Preclinical


Preclinical—drug dependence Preclinical—drug dependence Preclinical—drug dependence suggested that the low incidence of side effects could be the result of poor central accessibility (e.g., ref. 2). However, this explanation is not fully satisfactory given the host of effects produced by these agents upon systemic administration in animal models of neuropsychiatric disease. Several newer compounds have been developed with high potency and good central activity after systemic administration (e.g., NMCQX, NMDX, and L-698,544). It remains to been seen if these agents also display favorable side-effect profiles. Another possible explanation for the improved tolerability of glycine-site antagonists is that they could selectively interact with specific NMDA receptor subtypes that are expressed in distinct neuronal populations in a regionally specific fashion (see ref. 2). For example, the glycine-site antagonist CGP 61594 appears to selectively target NMDA receptors containing the NR2B subunit (62). Moreover, agents with partial agonist activity may have better tolerability than full antagonists.

Because at least some glycine-site ligands have actions at other sites, these additional actions may contribute to their pharmacological effects. For example, quinoxaline ligands such as NMCQX and NMDX also have affinity for AMPA receptors, albeit at slightly higher micromolar concentrations and L-698,544 exhibits good systemic activity (cf. ref. 63), but this compound also interacts with the glutamate (Kb, 6.7 |M) and AMPA (Kb, 9.2 |M) recognition sites with somewhat lower affinity than for the glycine site (IC50, 0.41 |M). Therefore, the efficacy of such agents in vivo might be due to competitive blockade of NMDA or AMPA receptors. Note, however, that the additional actions of compounds like these may provide a therapeutic advantage.

Like the neurotransmitter glutamate, glycine-site agonists enhance the opening of NMDA receptors (64). Such agonists would therefore oppose the actions of NMDA antagonists and may specifically promote the dissociation of use-dependent blockers such as uncompetitive antagonists (65-67). Consequently, glycine-site agonists can theoretically modulate responses to NMDA-receptor blockers, and in behavioral studies, glycine and glycine-site agonists d-serine and d-alanine have been shown to antagonize the stereotypies, ataxia, and locomotor stimulation produced by PCP and dizocilpine (68-72). However, d-serine does not block the subjective effects of PCP as measured in rats discriminating PCP from saline (60).

Table 4

Some Selective Antagonists of NMDA Receptor Isoforms Containing NR2B Subunits


Clinical status


Eliprodil (SL 82.0715)

Marketed (outside US)—peripheral vascular disease

Prior development—stroke, traumatic brain injury

In development—stroke


In development—epilepsy


Prior investigation—epilepsy

CP-101,606 Ro 25-6981

Conantokin G

Felbamate ADCI

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