ETHYLAMINES WITH HIGH AFFINITY AND SELECTIVITY FOR SIGMA RECEPTORS ATTENUATE COCAINE‐INDUCED BEHAVIORS IN MICE

Abstract

There are currently no effective pharmacotherapies for the treatment of cocaine abuse. Earlier studies demonstrated that cocaine interacts with σ receptors, and that antagonism of these proteins can attenuate the toxic and psychomotor stimulant effects of cocaine. In the present study, three ethylamines (AC927, BD1063 and UMB90) were characterized in radioligand binding and behavioral studies. In binding studies, all three ethylamines had nanomolar affinities for σ receptors. AC927 did not discriminate between the two σ receptor subtypes, but the 3,4-dichloro substituted compounds, BD1063 and UMB90, exhibited preferential affinity for σ1 over σ2 receptors. All three compounds exhibited selectivity for σ receptors when compared to seven additional binding sites, which included monoamine transporters and a select group of receptors. In behavioral studies, the ethylamines significantly attenuated cocaine-induced convulsions, lethality, locomotor activity, and conditioned place preference in mice. The anti-cocaine actions of the ethylamines were produced at doses that alone had no significant effects on behavior. Together with earlier studies, the present data suggest that simple ethylamines, such as AC927, BD1063, and UMB90, can mitigate the behavioral actions of cocaine through antagonism of σ receptors.