Sigma receptors are saturable, high affinity binding sites for several important classes of psychotropic drugs including typical antipsychotic, antidepressant, anticonvulsant, and psychotomimetic compounds. They are likely to contribute to the beneficial and/or side-effect profile of these compounds. Our laboratory has developed several new ligands for these receptors, which include antagonists, sigma-2 selective compounds, and ligands with potential as imaging agents. Characterization of two sigma antagonists with antidystonic effects in rats; The novel sigma 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. 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 di-0-tolylguanidine (DTG) and haloperidol. Both ligands shifted the dose curve for DTG to the right. BD1047 and BD1063 appear to act as antagonists at sigma sites. Ibogaine and its congeners are sigma-2 receptor-selective ligands with moderate affinity. Ibogaine exhibited moderate affinity for sigma-2 sites (Ki = 201 nM) and low affinity for sigma-1 sites (Ki =8,554 nM), thus showing 43-fold selectivity for sigma-2 receptors. The congeners tabernanthine and racemic ibogamine had sigma-2 Ki = 194 nM and 137 nM, respectively. However, they showed 3- to 5-fold higher sigma-1 affinity compared to ibogaine, resulting in about 14-fold selectivity for sigma-2 sites over sigma-1. A potential ibogaine metabolite, O-des-methyl ibogaine, had markedly reduced sigma-2 affinity relative to ibogaine (Ki + 5,226 nM) and also lacked significant affinity for sigma-1 sites. Thus sigma-2 receptors may play a role in the actions of ibogaine.
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