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

The novel sigma receptor ligands, ophenyl)ethyl]-N-methyl-2(dimethylam ino)ethylamine (BD1047) and 1-[2(3,4-dichlorophenyl)ethyl]-4-methylpip erazine (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 tes ted receptors (opiate, phencyclidine, muscarinic, dopamine, alpha(1)-, alpha(2)-, beta-adrenoceptor, 5-HT1, 5-HT2); the only exception was t he affinity of BD1047 for beta-adrenoceptors. Competition assays furth er revealed that the drugs interacted with both sigma(1) and sigma(2) binding sites. Although both drugs had preferential affinities for sig ma(1) sites, BD1047 exhibited a higher affinity for sigma(2) sites tha n BD1063. In behavioral studies, BD1047 and BD1063 had no effects on t heir own when unilaterally microinjected into the red nucleus of rats, but both compounds attenuated the dystonia produced by the high affin ity sigma ligands, di-o-tolylguanidine (DTG) and haloperidol. BD1047 a nd BD1063 dose-dependently attenuated the dystonia produced by DTG, su ggesting 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 wi th sigma binding sites.