Synthesis of (+)-cis-N-(4-isothiocyanatobenzyl)-N-normetazocine, an isothiocyanate derivative of N-benzylnormetazocine as acylant agent for the sigma(1) receptor

(+)-cis-N-(4-isothiocyanatobenzyl)-N-normetazocine (BNIT) (+)-(4) was designed and synthesized as a derivative of the potent and selective σ1 receptor ligand (+)-cis-N-benzyl-Nnormetazocine for irreversibly blocking σ1 binding sites. Pretreatment of guinea pig brain membranes with BNIT (0.1, 1, and 5 μM) caused a concentration-dependent loss of binding of the selective σ1 ligand [3H]-(+)-pentazocine. Binding experiments with [3H]-1,3-di(2-tolyl)guanidine ([3H]-DTG), a ligand of σ1 and σ2 receptors, showed that pretreatment with BNIT blocked only the σ1 component of [3H]-DTG binding.