SYNTHESES AND CONFORMATIONAL-ANALYSES OF GLUTAMATE ANALOGS - 2-(2-CARBOXY-3-SUBSTITUTED-CYCLOPROPYL) GLYCINES AS USEFUL PROBES FOR EXCITATORY AMINO-ACID RECEPTORS

An hypothesis that each subtype of glutamate receptors requires a spec ific conformation of L-glutamate for its selective activation was exam ined using the conformationally constrained analogs of L-glutamate, L- 2-(2-carboxycyclopropyl)glycines (CCGs), and -2-[2-carboxy-3(methoxyme thyl)cyclopropyl]glycines (MCGs). All MCG isomers were newly synthesiz ed in a stereoselective manner via the common synthetic intermediate 5 a starting with the oxazolidine aldehyde 1. The synthesis of the four MCG isomers was characterized by a stereoselective inversion of alpha- cyclopropyl acyl anion (e.g., from 10 to 11). The spectroscopic studie s, in particular, pH vs J correlation experiments of CCGs and MCGs usi ng H-1 NMR and their molecular mechanics calculations, revealed that t hese analogs possessed an antiperiplanar conformation regarding the H- C2-C1'-H bond as a majority among the other possible rotamers in aqueo us solution. The fact that each CCG and MCG exhibited potent and selec tive activities to the distinct types of glutamate receptors allowed u s to extract an active conformation of L-glutamate. Thus, the conforma tional requirement of metabotropic glutamate receptors was speculated to be the anti-anti conformation (aa-A) because the conformations of C CG-I and cis and trans-MCG-I, selective agonists of the receptors, clo sely mimicked the rotamer A of L-glutamate. On the other hand, N-methy l-D-aspartate and kainate receptors, representative ionotropic glutama te receptors, would require glutamate g(+)g(+) rotamer E which was ded uced from the conformation-activity relationship studies of the select ive agonists CCG-IV, cis-MCG-IV, and trans-MCG-IV and the related anal ogs.