Pharmacology and toxicology of ATOA, an AMPA receptor antagonist and a partial agonist at GluR5 receptors

Abstract

( RS)-2-Amino-3-[3-(carboxymethoxy)-5- tert-butyl-4-isoxazolyl]propionic acid (ATOA) has previously been described as an antagonist at ( RS)-2-amino-3-(3-hydroxy-5-methyl-4-isoxazolyl)propionic acid (AMPA) receptors with an IC 50 value of 150 μM towards AMPA-induced depolarisation in the rat cortical wedge preparation. ATOA has now been shown also to be a partial agonist at recombinant GluR5 receptors, expressed in Xenopus oocytes, with an EC 50 value of 170 μM and a relative efficacy of 0.17±0.04 compared with responses produced by kainic acid (1.0). Using cultured cerebral cortical neurones as a test system and leakage of lactate dehydrogenase (LDH) as an indicator of cell damage, ATOA was shown to be cytotoxic (ED 50 >300 μM), though much less toxic than the structurally related dual AMPA and GluR5 agonist, ( RS)-2-amino-3-(3-hydroxy-5- tert-butyl-4-isoxazolyl)propionic acid (ATPA) (ED 50=14±2 μM). The toxic effect of ATPA was sensitive to 6,7-dinitroquinoxaline-2,3-dione (DNQX) but was not significantly reduced by the selective AMPA receptor antagonist, (RS)-2-amino-3-[3-(carboxymethoxy)-5-methyl-4-isoxazolyl]propionic acid (AMOA). The toxicity of ATOA (1 mM) could not be significantly attenuated by co-administration of AMOA (300 μM) or DNQX (25 μM). A structure–activity analysis indicates that the tert-butyl group of ATPA and ATOA facilitates the interaction of these compounds with GluR5 receptors.