Excitatory amino acids. Synthesis of (RS)-2-amino-3-(5-cyclopropyl-3-hydroxyisoxazol-4-yl)propionic acid, a new potent and specific AMPA receptor agonist

Abstract

The synthesis of (RS)-2-amino-3-(5-cyclopropyl-3-hydroxyisoxazol-4-yl)propionic acid 6, an analogue of the AMPA receptor agonist (RS)-2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl)-propionic acid, AMPA, 3 is described. Compound 6 has been studied in vitro in radioligand binding and electrophysiological test systems and shown to be a specific AMPA receptor agonist equipotent with AMPA. The synthesis of 6 was based on 5-cyclopropyl-3-hydroxyisoxazole 8, which was converted into the intermediate 4-bromomethyl-5-(3-bromopropyl)-2-methoxymethyl-2,3-dihydroisoxazol-3-one 9 by opening of the cyclopropane ring. Based on ¹H and ¹³C NMR data, this conversion has been shown to proceed stepwise, the progression of the different steps being dependent on the concentration of the hydrobromic acid medium, reaction time, and temperature. An acetamidomalonate group has been regiospecifically substituted for the allylic bromine atom of 9 to give 10, and treatment of 10 with sodium hydride gave compound 11 containing a cyclopropyl group, reformed by cyclization of the 3-bromopropyl substituent of 10. Compound 11 has been fully deprotected by treatment with aqueous trifluoroacetic acid to give 6.