Effects of a centrally active benzoylpiperidine drug on α-amino-3-hydroxy-5-methyl-4-isoxalepropionic acid receptor kinetics

Abstract A newly developed benzoylpiperidine drug that increases the size of fast, excitatory synaptic responses was examined for its effects on the kinetic properties of α-amino-3-hydroxy-5-methyl-4-isoxalepropionic acid-type glutamate receptors. When long pulses of glutamate were applied to excised hippocampal patches of the rat, the compound [1-(1,3-benzodioxol-5-ylcarbonyl)piperidine-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, 1-(1,3-benzodioxol-5-ylcarbonyl)piperidine-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 1-(1,3-benzodioxol-5-ylcarbonyl)piperidine-20 causes a measurable increase in the affinity of α-amino-3-hydroxy-5-methyl-4-isoxalepropionic acid receptors; the ec 50 values for this effect were similar to those obtained in excised patch studies. The actions of 1-(1,3-benzodioxol-5-ylcarbonyl)piperidine-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 benzoylpiperidine compounds were qualitatively different from those obtained with cyclothiazide, although both types of drug increased α-amino-3-hydroxy-5-methyl-4-isoxalepropionic acid receptor-mediated synaptic responses. Moreover, interactions between the drugs were at most only partially competitive; α-amino-3-hydroxy-5-methyl-4-isoxalepropionic acid receptors may thus have multiple modulatory sites with distinct drug preferences and different effects on receptor kinetics.