Ibotenic acid analogues. Synthesis and biological testing of two bicyclic 3-isoxazolol amino acids.

Abstract

The bicyclic 3-isoxazolol amino acids (RS)-3-hydroxy-4,5,6,7-tetrahydroisoxazolo[4,5-c]pyridine-4-carboxylic acid (5, 4-HPCA) and (RS)-3-hydroxy-4,5,6,7-tetrahydroisoxazolo[4,5-c]pyridine-6-carboxylic acid (11, 6-HPCA) were synthesized as model compounds for studies of the structural requirements of central excitatory amino acid neurotransmitter receptors. 4-HPCA was synthesized via introduction of a methoxycarbonyl group into the 4-position of the lithiated N-nitroso intermediate 1. The key reaction in the synthesis of 6-HPCA is an intramolecular N-alkylation of the appropriately substituted acetamidomalonate derivative 7 using sodium hydride as a base. On the basis of the pKA values for 4-HPCA the existence of an intramolecular hydrogen bond in the zwitterionic form of this amino acid is proposed. 6-HPCA was shown by 1H NMR spectroscopy to adopt preferentially a conformation with the carboxylate group in an equatorial position. 4- and 6-HPCA were tested as agonists and antagonists at excitatory amino acid receptors on neurones in the cat spinal cord using microelectrophoretic techniques. Neither compound showed significant effects at these receptors.