SYNTHESIS AND PHARMACOLOGY OF N-ALKYLATED DERIVATIVES OF THE EXCITOTOXIN IBOTENIC ACID

Three amino-alkylated derivatives of the naturally occurring excitator y amino acid (EAA) receptor agonist ibotenic acid (Ibo) have been synt hesized and tested pharmacologically. N-Methyl-Ibo (la) and N-ethyl-Ib o(lb) were shown to be agonists at NMDA receptors (EC50 = 140 and 320 mu M, respectively), though with activities considerably lower than Ib o (EC50 = 9.6 mu M). N-Benzyl-Ibo (Ic) was inactive at ionotropic EAA receptors and all three compounds were, in contrast to Ibo, inactive a t metabotropic EAA receptors. Molecular mechanics calculations have be en performed on Ibo, la-c and the potent NMDA agonist 2-amino-2-(3-hyd roxy-5-methyl-4-isoxazolyl)acetic acid (AMAA) in order to elucidate th e observed structure-activity data. (C) 1998 Elsevier Science Ltd. All rights reserved.