Synthesis and Structure-Activity Studies on Excitatory Amino Acids Structurally Related to Ibotenic Acid

Abstract

With use of ibotenic acid as a lead, analog of (Rs)-.alpha.-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) and of (RS)-3-hydroxy-4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridine-7-carboxylic acid (7-HPCA) were synthesized and tested as excitants of neurons in the cat spinal cord by using microelectrophoretic techniques and as inhibitors of the binding of kainic acid in vitro. Like AMPA and 7-HPCA, (RS)-3-hydroxy-4,5,6,7-tetrahydroisoxazolo[5,4-c]-pyridine-5-carboxylic acid (10, 5-HPCA) and (RS)-3-hydroxy-5-(bromomethyl)isoxazole-4-propionic acid (11, ABPA) proved to interact potently and selectively with central quisqualic acid receptors, assumed to represent physiological glutamic acid receptors. Analogs of 7-HPCA or 10, in which one or both of the acid groups were masked, were very weak or inactive as neuronal excitants and had no antagonistic effects at excitatory amino acid receptors. The structure of 7-HPCA in the crystalline state was established by X-ray analyses. The preferred conformation of 10 in aqueous solution was determined by 1H NMR spectroscopy. 7-HPCA as well as 10 adopted preferentially conformations with the carboxylate groups in equatorial positions. AMPA, 7-HPCA, and 10 may interact with quisqualic acid receptors in conformations essentially reflecting active conformation(s) of glutamic acid at these receptors.