[H-3] OPIPRAMOL LABELS A NOVEL BINDING-SITE AND SIGMA RECEPTORS IN RAT-BRAIN MEMBRANES

Opipramol (OP), a clinically effective antidepressant with a tricyclic structure, is inactive as an inhibitor of biogenic amine uptake. [H-3]Opipramol binds saturably to rat brain membranes (apparent K(D) = 4 nM, B(max) = 3 pmol/mg of protein). [H-3]Opipramol binding can be differentiated into haloperidol-sensitive and -resistant components, with K(i) values for haloperidol of 1 nM (B(max) = 1 pmol/mg of protein) and 350 nM (B(max) = 1.9 pmol/mg of protein), respectively. The drug specificity of the haloperidol-sensitive component is the same as that of sigma receptors labeled with (+)-[H-3]3-(3-hydroxyphenyl)-N-(1-propyl)piperidine. The haloperidol-resistant component does not correspond to any known neurotransmitter receptor or uptake recognition site. It displays high affinity for phenothiazines and related structures such as perphenazine, clopenthixol, and flupenthixol, whose potencies are comparable to that of opipramol. Because certain of these drugs are more potent at the haloperidol-resistant opipramol site than in exerting any other action, it is possible that this opipramol-selective site may mediate their therapeutic effects.