Synthesis and pharmacological evaluation of novel conformationally constrained homologues of glutamic acid

Twelve novel conformationally constrained homologues of glutamic acid have been synthesized and pharmacologically characterized at ionotropic glutamate receptors (iGluRs). Synthesis of the target compounds involved 1,3-dipolar cycloaddition of nitrile oxides to suitable dipolarophiles. The structure to the compounds has been assigned by 1H NMR and, in the case of derivatives (±)-4a, (±)-4b, (±)-5a, and (±)-5b, by means of an X-ray crystallographic analysis carried out on intermediate (±)-12a. The synthesized amino acids were found to be without affinity (Ki/IC50 > 100 μM) for iGluRs with the exception of compounds (±)-4b and (±)-5b, which showed a modest affinity for NMDA receptors (Ki = 34 and 13 μM, respectively). The results indicate that the increased conformational constraints introduced by the cyclopropane ring and the spiro-attached proline ring are both detrimental to the pharmacological activity.