Design of Cyclopentaisoxazoline Amino Acids as Conformationally Constrained Agonists at Glutamate Receptors

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 (EC50 = 79 µM), 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].