FUNCTIONAL PARTIAL AGONISM AT IONOTROPIC EXCITATORY AMINO-ACID RECEPTORS

Amino-3-(3-hydroxy-5-phenyl-4-isoxazolyl)propionic acid (APPA), which is an analogue of amino-3-(3-hydroxy-5-methyl-4-isoxazolyl)propionic a cid (AMPA), shows the characteristics of a partial AMPA receptor agoni st. Since (S)-APPA is a full AMPA agonist and (R)-APPA a competitive a ntagonist, the partial agonism observed for APPA, which is a 1:1 mixtu re of (S)- and (R)-APPA, is only apparent. These observations have pro mpted comparative pharmacological studies of different molar ratios of a series of AMPA and N-methyl-D-aspartic acid (NMDA) agonists and res pective competitive antagonists, and of these agonists in the presence of fixed concentrations of antagonist. Using the rat cortical wedge p reparation, the latter series of experiments showed the expected right ward parallel shifts of the dose-response curves. The former type of e xperiments, on the other hand, produced dose-response curves at differ ent levels of maximal response, depending on the molar ratios of agoni st and antagonist used. This phenomenon, which is in agreement with th e theory for competitive receptor interaction, has been termed functio nal partial agonism, a new pharmacological concept of potential therap eutic utility. These results were obtained using AMPA, the AMPA agonis t o-3-(5-tert-butyl-3-hydroxy-4-isoxazolyl)propionic acid (ATPA), the competitive AMPA antagonists -(3-carboxymethoxy-5-methyl-4-isoxazolyl) propionic acid (AMOA) and 6-nitro-7-sulfamoylbenzo[f]quinoxalin-2,3-di one (NBQX), NMDA, and the competitive NMDA antagonist RS)-3-(2-carboxy -4-piperazinyl)propyl-1-phosphonic acid (CPP). Copyright (C) 1996 Else vier Science Ltd.