Synthesis and pharmacological characterization at glutamate receptors of erythro- and threo-tricholomic acid and homologues thereof |
| |
Authors: | Paola Conti Gabriella Roda Lucia Tamborini Birgitte Nielsen Carlo De Micheli |
| |
Institution: | a Istituto di Chimica Farmaceutica e Tossicologica ‘P. Pratesi’, Università degli Studi di Milano, Viale Abruzzi 42, 20131 Milano, Italy b Department of Medicinal Chemistry, The Danish University of Pharmaceutical Sciences, Universitetsparken 2, DK-2100 Copenhagen, Denmark |
| |
Abstract: | The erythro- and threo-amino-(3′-hydroxy-4′,5′-dihydro-isoxazol-5′-yl)-acetic acids, stereoisomers of tricholomic acid, were synthesized along with the corresponding higher homologues erythro- and threo-amino-(3′-carboxy-4′,5′-dihydro-isoxazol-5′-yl)-acetic acids. The target compounds were prepared via the 1,3-dipolar cycloaddition of a suitable nitrile oxide to (±)-2-tert-butoxycarbonylamino-3-buten-1-ol. Such a strategy allowed the synthesis of the two stereoisomeric amino acids in comparable amounts. The pharmacological activity of these compounds was investigated at ionotropic and metabotropic glutamate receptors (iGluRs and mGluRs) by means of receptor binding assays to rat cortical membranes, electrophysiological tests and second messenger assays at cloned receptors expressed in CHO cells. Their pharmacological profiles were compared to those of l-glutamate and of the previously described selective NMDA receptor antagonists 5-(2-amino-2-carboxyethyl)-4,5-dihydroisoxazole-3-carboxylic acids in order to highlight the effect of increasing/reducing the distance between the amino acid moiety and the distal acid group, which represent the two pharmacophoric entities. |
| |
Keywords: | Tricholomic acid Ionotropic glutamate receptors Metabotropic glutamate receptors 1 3-Dipolar cycloaddition |
本文献已被 ScienceDirect 等数据库收录! |
|