Over activation of the NMDA receptor complex has been implicated in a number of neurological conditions. The use of NMDA antagonists as therapeutic agents has been limited by serious cognitive and motor side effects. Significant efforts have been reported in the development of NR2B subtype-selective antagonists, which have shown efficacy without the side effects observed with nonspecific NMDA antagonists. Classical ifenprodil-like molecules containing benzyl- and phenylpiperidines attached to a phenol or an appropriate isostere by a linker have provided valuable chemical leads as potential therapeutic agents. In this review, recent efforts in the discovery and development of structurally unique NR2B subtype-selective NMDA antagonists that do not fit the classical "ifenprodil-like" pharmacophore will be discussed.

A series of 3-substituted aminocyclopentanes has been identified as highly potent and selective NR2B receptor antagonists. Incorporation of a 1,2,4-oxadiazole linker and substitution of the pendant phenyl ring led to the discovery of orally bioavailable analogues that showed efficient NR2B receptor occupancy in rats. Unlike nonselective NMDA antagonists, the NR2B-selective antagonist 22 showed no adverse affects on motor coordination in the rotarod assay at high dose. Compound 22 was efficacious following oral administration in a spinal nerve ligation model of neuropathic pain and in an acute model of Parkinson's disease in a dose dependent manner.

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