European Journal of Medicinal Chemistry 2007-08-01

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

Paola Conti, Antonio Caligiuri, Andrea Pinto, Gabriella Roda, Lucia Tamborini, Birgitte Nielsen, Ulf Madsen, Karla Frydenvang, Alessio Colombo, Carlo De Micheli

Index: Eur. J. Med. Chem. 42 , 1059-68, (2007)

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Abstract

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 (1)H 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 (K(i)/IC(50)>100microM) for iGluRs with the exception of compounds (+/-)-4b and (+/-)-5b, which showed a modest affinity for NMDA receptors (K(i)=34 and 13microM, 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.