Rigid analogs of ACPD have been synthesized to mimick different potential conformations of ACPD in aqueous solution. One of them, (+)-ABHD-I is a competitive antagonist at mGluRla receptor with a KB value of 300 laM. Glutamic acid is a major excitatory amino acid and neurotransmitter in the central nervous system. It mediates fast synaptic transmission in the brain and probably has some role in neurodegenerative disorders. It is generally admitted that L-glutamic acid, a flexible molecule, displays different bioactive conformations depending on each type of glutamate receptors. 1 Five classes 2 have been identified and named according to their selective agonists: NMDA (N-methyl-D-aspartic acid), AMPA (L-2-amino-3-(3-hydroxy-5-methyl-4-isoxazolyl)propionic acid, KA (kainic acid), ACPD (1S,3R-l-amino-cyclopentane-1,3-dicarboxylic acid), and L-AP4 (L-2-amino-4phosphonobutyric acid).
The ACPD-receptor family is represented by several G-protein coupled receptors (metabotropic glutamate receptors or mGluR) 3'4 which mediate a variety of transduction mechanisms, including stimulation of phosphoinositide hydrolysis (mGluR1, mGluR5), or inhibition of adenylyl-cyclase (mGluR2, mGluR3). 1S,3R-ACPD, one of the few specific ligands of these glutamate receptor subtypes, has been considered as one of the possible conformationally-rigid analogs of glutamic acid. 5"7 However, in a recent study by NMR and molecular dynamics, it has been shown 8 that both cis-and trans-isomers of ACPD are rather flexible, and can adopt various envelop (E) conformations which have been classified in four types (I-IV), according to their aamino/7-carboxy groups (dl) and a-carboxy/y-carboxy groups (d2) distances. The most populated conformation (El) of 1S,3R-ACPD, in aqueous solution at pH 7.0 seems to be quite different from what is generally accepted as the "extended" bioactive conformation of ACPD (1E) for metabotropic receptors. 1'9 CO 2" ~ NH3* C02" " O2C~ . O2 c NH3 +