Structure–activity comparison of YZ-069, a novel σ ligand, and four analogs in receptor binding and behavioral studies

Abstract

Earlier studies show that antagonism of σ receptors using high to moderate affinity compounds or antisense oligodeoxynucleotides targeting the σ 1 subtype significantly attenuates the behavioral effects of cocaine in mice. In this study, the novel σ receptor ligand YZ-069 [ N-phenylpropyl- N′-(3,4-dichlorophenethyl)piperazine] and four analogs (representing nitrophenyl and methoxyphenyl derivatives) were evaluated in receptor binding and behavioral studies to further delineate structural features that convey favorable anticocaine actions. In receptor binding studies, all of the compounds had low nanomolar affinities for σ 1 and σ 2 receptors but only micromolar affinities for monoamine transporters. Consistent with the favorable affinities of the compounds for σ receptors, they also significantly attenuated cocaine-induced convulsions in mice. The compounds with the 3,4-dichlorophenyl and methoxyphenyl substitutions provided better protection against cocaine-induced convulsions than the nitrophenyl derivative. This is consistent with the reduced lipophilicity of the nitro substitution, which would reduce its ability to cross the blood–brain barrier. The position of the substituent on the phenyl ring had no significant effect on binding affinity or behavioral protective actions. Together with earlier studies, the data suggest that favorable features of σ receptor ligands with anticocaine actions include high affinity for brain σ receptors, antagonistic actions at the receptor, and lipophilicity to facilitate crossing the blood–brain barrier.