Subtype-selective N-methyl-D-aspartate receptor antagonists: benzimidazalone and hydantoin as phenol replacements

Abstract

Previous work in our laboratories investigating compounds with structural similarity to ifenprodil (5) and 6 (CP101,606) resulted in compound 7 as a potent and selective antagonist of the NR1/2B subtype of the NMDA receptors. Replacement of the phenol group of 7 with a benzimidazalone group tethered by a three-carbon chain to 4-benzylpiperidine resulted in a slightly less active, but selective, compound. Lengthening the carbon tether resulted in a decrease in NR1/2B potency. Replacement of the phenol ring with a hydantoin resulted in weak antagonists. Compound 11a was one of the most potent NR1/2B antagonists from this study. Compound 11a also potentiated the effects of L-DOPA in a rat model of Parkinson's disease (the 6-hydroxydopamine-lesioned rat), dosed at 30 mg/kg orally.