The Third Line of Positive Allosteric Modulators for AMPA Receptors

Abstract

AMPA-type glutamate receptors are important molecules in central excitatory synaptic transmission. On AMPA receptor molecules, there are allosteric modulatory sites that are different from a glutamate-binding site. Drugs that are called allosteric potentiators stimulate one of the allosteric modulatory sites. Aniracetam, cyclothiaizde, and their derivertives have been known as the potentiators (Ito et al. 1990; Patneau et al. 1993; Yamada and Tang 1993). It is reported that cyclothiazide facilitates release of dopamine through modulation of AMPA receptors in cultured neuronal cells (Petitet et al. 1995). This suggests that the allosteric potentiators have potential as modulators of doparninergic slow synaptic transmissions by modulating the release of dopamine via modulation of AMPA receptor activity. In addition, it is important that these potentiators are nootropic. However, studies about positive allosteric modulators of AMPA receptors are not mature yet when compared with the studies about a benzodiazepine site, an allosteric modulatory site on GABA receptors. Many drugs that act on the benzodiazepine site have been developed, and actions of each drug upon the receptor activity and animal behavior are studied in detail.