Premium
Design of Cyclopentaisoxazoline Amino Acids as Conformationally Constrained Agonists at Glutamate Receptors
Author(s) -
Conti Paola,
De Amici Marco,
Grazioso Giovanni,
Roda Gabriella,
Stensbøl Tine B.,
BräunerOsborne Hans,
Madsen Ulf,
Toma Lucio,
De Micheli Carlo
Publication year - 2003
Publication title -
european journal of organic chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.825
H-Index - 155
eISSN - 1099-0690
pISSN - 1434-193X
DOI - 10.1002/ejoc.200300424
Subject(s) - chemistry , acpd , metabotropic glutamate receptor , ionotropic effect , metabotropic glutamate receptor 5 , metabotropic glutamate receptor 1 , metabotropic glutamate receptor 2 , glutamate receptor , agonist , stereochemistry , nmda receptor , metabotropic receptor , amino acid , glutamic acid , receptor , biochemistry
We have prepared four isomeric 3‐hydroxycyclopentaisoxazoline amino acids 12 − 15 , which represent analogues of glutamic acid having restricted conformations, through a strategy based on the 1,3‐dipolar cycloaddition of bromonitrile oxide to a suitably protected 1‐aminocyclopent‐2‐enecarboxylic acid. These target compounds proved to be inactive when assayed at ionotropic and metabotropic glutamate receptors, except for 12 which is an agonist primarily at mGluR5 (EC 50 = 79 μ M ), but is less active at mGluR2 and only marginally active at mGluR1. The biological data are accounted for through comparison of the conformational profiles of the test compounds with that of reference agonists, i.e., N ‐methyl‐ D ‐aspartate (NMDA, 2 ), and 1‐aminocyclopentane‐1,3‐dicarboxylic acids [ trans ‐ACPD, 10 ; cis ‐ACPD, 11 ]. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2003)