Synthesis and pharmacological evaluation of novel conformationally constrained homologues of glutamic acid
Articolo
Data di Pubblicazione:
2007
Citazione:
Synthesis and pharmacological evaluation of novel conformationally constrained homologues of glutamic acid / P. Conti, C. Antonio, A. Pinto, G. Roda, L. Tamborini, N. Birgitte, M. Ulf, F. Karla, A. Colombo, C. De Micheli. - In: EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY. - ISSN 0223-5234. - 42:8(2007), pp. 1059-1068. [10.1016/j.ejmech.2007.01.013]
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 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.
Tipologia IRIS:
01 - Articolo su periodico
Keywords:
Glutamic acid homologues; Ionotropic glutamate receptors; Isoxazoline derivatives; Spirocyclic compounds
Elenco autori:
P. Conti, C. Antonio, A. Pinto, G. Roda, L. Tamborini, N. Birgitte, M. Ulf, F. Karla, A. Colombo, C. De Micheli
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