Synthesis and pharmacology of 3-hydroxy-Δ2-isoxazoline-cyclopentane analogues of glutamic acid

The synthesis and pharmacology of two potential glutamic acid receptor ligands are described. Preparation of the bicyclic 3-hydroxy-Δ2-isoxazoline-cyclopentane derivatives (±)-7 and (±)-8 was accomplished via 1,3-dipolar cycloaddition of bromonitrile oxide to suitably protected 1-amino-cyclopent-3-enecarboxylic acids. Their structure was established using a combination of 1H NMR spectroscopy and molecular mechanics calculations carried out on the intermediate cycloadducts (±)-11 and (±)-12. Amino acid derivatives (±)-7 and (±)-8 were assayed at ionotropic and metabotropic glutamic acid receptor subtypes and their activity compared with that of trans-ACPD and cis-ACPD. The results show that the replacement of the ω-carboxylic group of the model compounds with the 3-hydroxy-Δ2-isoxazoline moiety abolishes or reduces drastically the activity at the metabotropic glutamate receptors. Conversely, on passing from cis-ACPD to derivative (±)-8, the agonist activity at NMDA receptors is almost unaffected.