3-Carboxy-4-phosphonocyclopentane amino acids: New metabotropic glutamate receptor ligands

Summary.  Two glutamic acid analogs (1SR,3RS,4RS)- and (1SR,3SR,4SR)-1-amino-4-phosphono cyclopentane-1,3-dicarboxylic acids (APCPD) have been synthesized. Pure E-(diethoxy-phosphoryl)-acrylic acid ethyl ester was obtained from ethyl propiolate, phenol and triethylphosphite. It was used as dienophile in a Diels-Alder reaction. Oxidation and cyclization afforded 3-(ethoxy-carbonyl)-4-(diethoxy-phosphoryl)-cyclopentanone. Bucherer-Bergs reaction and hydrolysis yielded APCPD-III and -IV which are inactive on mGlu1a receptor and antagonists on mGlu2 and mGlu8a receptors. Received April 2, 2002 Accepted July 11, 2002 Published online December 18, 2002 Acknowledgments This work was supported by grants from the CNRS, the programs “Physique et Chimie du Vivant” (PCV00–134, CNRS) and “Molécules et Cibles Thérapeutiques” (CNRS/INSERM), RETINA France and the Fondation de France (Comité Parkinson). A.-S. B. was supported by fundings from Parke-Davis Pharmaceutical Research (Ann Arbor, MI) and the Fondation de la Recherche Médicale. Authors' address: Dr Francine C. Acher, Laboratoire de Chimie et Biochimie Pharmacologiques et Toxicologiques, UMR8601-CNRS, Université René Descartes-Paris V, 45 rue des Saints-Pères, 75270 Paris Cedex 06, France, Fax: (33) 1 42 86 83 87, E-mail: acher@biomedicale.univ-paris5.fr