CHARACTERIZATION OF 2 NOVEL SIGMA-RECEPTOR LIGANDS - ANTIDYSTONIC EFFECTS IN RATS SUGGEST SIGMA-RECEPTOR ANTAGONISM

The novel sigma receptor ligands, N-[2-(3,4-dichlorophenyl)ethyl]-N-methyl-2(dimethylamino)ethylamine (BD1047) and 1-[2(3,4-dichlorophenyl)ethyl]-4-methylpiperazine (BD1063), were characterized in rats using binding assays and behavioral studies. In radioligand binding studies, the novel ligands showed marked selectivity for sigma binding sites, generally having a 100-fold or better affinity for sigma sites compared to nine other tested receptors (opiate, phencyclidine, muscarinic, dopamine, alpha(1)-, alpha(2)-, beta-adrenoceptor, 5-HT1, 5-HT2); the only exception was the affinity of BD1047 for beta-adrenoceptors. Competition assays further revealed that the drugs interacted with both sigma(1) and sigma(2) binding sites. Although both drugs had preferential affinities for sigma(1) sites, BD1047 exhibited a higher affinity for sigma(2) sites than BD1063. In behavioral studies, BD1047 and BD1063 had no effects on their own when unilaterally microinjected into the red nucleus of rats, but both compounds attenuated the dystonia produced by the high affinity sigma ligands, di-o-tolylguanidine (DTG) and haloperidol. BD1047 and BD1063 dose-dependently attenuated the dystonia produced by DTG, suggesting a receptor-mediated mechanism, and the dose curve for DTG was shifted to the right in the presence of the novel ligands. BD1047 and BD1063 appear to act as antagonists at sigma sites and may represent promising new tools for probing other functional effects associated with sigma binding sites.