Effects of five-membered ring conformation on bioreceptor recognition: identification of 3R-amino-1-hydroxy-4R-methylpyrrolidin-2-one (L-687,414) as a potent glycine/N-methyl-D-aspartate receptor antagonist

Abstract

Syntheses of the 4-methyl (2 and 3) and [3.2.1]bicyclo (4 and 5) analogues of the glycine/N-methyl-D-aspartate (NMDA) antagonist 3-amino-1-hydroxypyrrolidin-2-one (HA-966, 1) provide evidence that glycine receptor recogntion requires the energetically less favoured 3-pseudoaxial conformation of the pyrrolidone ring, resulting in a 5–10 fold improvement in activity with the 3R-amino, 4R-methyl derivative (2a, L-687,414).