Effects of a centrally active benzoylpyrrolidine drug on AMPA receptor kinetics

Abstract

A newly developed benzoylpyrrolidine drug (BDP-20) that increases the size of fast, excitatory synaptic responses was examined for its effects on the kinetic properties of alpha-amino-3-hydroxy-5-methyl-4-isoxalepropionic 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 prolonged response deactivation by a factor of about four and greatly reduced the depression in the second response when two consecutive glutamate pulses were given. Two types of equilibrium binding assays indicated that BDP-20 causes a measurable increase in the affinity of AMPA receptors; the EC50 values for this effect were similar to those obtained in excised patch studies. The actions of BDP-20 on physiology and ligand binding could be adequately reproduced in a receptor model by slowing the rate of desensitization and increasing the affinity of the sensitized states. The biochemical and physiological effects of this benzoylpyrrolidine compound were qualitatively different from those obtained with cyclothiazide, although both types of drug increased AMPA receptor-mediated synaptic responses. Moreover, interactions between the drugs were at most only partially competitive; AMPA receptors may thus have multiple modulatory sites with distinct drug preferences and different effects on receptor kinetics.