Asymmetric synthesis of (2R, 1’S, 2’R, 3’S)-2-(2’- Carboxy-3’-phenylcyclopropyl)glicine (PCCG 13), the first selective antagonist of metabotropic glutamate receptors coupled phospholipase D

Activation of phospholipase D (PLD) represents an important mechanism leading to formation of diacylglycerol in brain tissue. It has recently been reported that, besides phospholipase C (PLC) and adenylyl cyclase (AC). metabotropic glutamate receptors (mGluRs) also stimulate PLD. In search for ligands to utilize as tools for the physiological characterization of this new class of mGluRs, the activity of a stereolibrary of sixteen 2-(2’- carboxy-3’-phenylcyclopropyl)glycines (PCCGs) on the PLDspecific transphosphatidylation reaction resulting in the formation of [3HJphosphatidyl-ethanol ([3H]-Pet) was examined. Among the tested diastereoisomers (2R, 1 ‘S, 2’R, 3’S)-PCCG 13 wss able to antagonize, with an I& of 25 nM, the formation of [‘HIPet induced by 100 pM (IS, 3R)-ACPD. In view of the relevance of(2R. 1’S, Z’R, 3’S)-PCCG I3 as a promising tool for the understanding the physiological role played by PLD-coupled mGluRs, we have undertaken its enantioselective synthesis starting from S-serine. The synthetic methodology, developed for the preparation of PCCG 13, as well as preliminary pharmacological data will be presented.