EFFECTS OF A CENTRALLY ACTIVE BENZOYLPYRROLIDINE DRUG ON AMPA RECEPTOR KINETICS

A newly developed benzoylpyrrolidine drug (BDP-20) that increases the size of fast, excitatory synaptic responses was examined for its effec ts on the kinetic properties of alpha-amino-3-hydroxy-5-methyl-4-isoxa lepropionic acid (AMPA)-type glutamate receptors. When long pulses of glutamate were applied to excised hippocampal patches of the rat, the compound BDP-20 caused an approximately 15-fold reduction in the rate at which responses desensitized and a similar size increase in steady- state currents. In experiments using 1-ms glutamate pulses, BDP-20 pro longed response deactivation by a factor of about four and greatly red uced the depression in the second response when two consecutive glutam ate pulses were given. Two types of equilibrium binding assays indicat ed that BDP-20 causes a measurable increase in the affinity of AMPA re ceptors; the EC(50) values for this effect were similar to those obtai ned in excised patch studies. The actions of BDP-20 on physiology and ligand binding could be adequately reproduced in a receptor model by s lowing the rate of desensitization and increasing the affinity of the sensitized states. The biochemical and physiological effects of this b enzoylpyrrolidine compound were qualitatively different from those obt ained with cyclothiazide, although both types of drug increased AMPA r eceptor-mediated synaptic responses. Moreover, interactions between th e drugs were at most only partially competitive; AMPA receptors may th us have multiple modulatory sites with distinct drug preferences and d ifferent effects on receptor kinetics. Copyright (C) 1996 IBRO.