EXCITATORY AMINO-ACIDS - SYNTHESIS OF -3-(5-CYCLOPROPYL-3-HYDROXYISOXAZOL-4-YL)PROPIONIC ACID, A NEW POTENT AND SPECIFIC AMPA RECEPTOR AGONIST

The synthesis of S)-2-amino-3-(5-cydopropyl-3-hydroxyisoxazol-4-yl) pr opionic acid 6, an analogue of the AMPA receptor agonist (RS)-2-amino- 3-(3-hydroxy-5-methylisoxazol-4-yl) propionic acid, AMPA, 3 is describ ed. Compound 6 has been studied in vitro in radioligand binding and el ectrophysiological test systems and shown to be a specific AMPA recept or agonist equipotent with AM PA. The synthesis of 6 was based on 5-cy clopropyl-3-hydroxyisoxazole 8, which was converted into the intermedi ate opropyl)-2-methoxymethyl-2,3-dihydroisoxazol-3-one 9 by opening of the cyclopropane ring. Based on H-1 and C-13 NMR data, this conversio n has been shown to proceed stepwise, the progression of the different steps being dependent on the concentration of the hydrobromic acid me dium, reaction time, and temperature. An acetamidomalonate group has b een regiospecifically substituted for the allylic bromine atom of 9 to give 10, and treatment of 10 with sodium hydride gave compound 11 con taining a cyclopropyl group, reformed by cyclization of the 3-bromopro pyl substituent of 10. Compound 11 has been fully deprotected by treat ment with aqueous trifluoroacetic acid to give 6.