Heterogeneous Binding of Sigma Radioligands in the Rat Brain and Liver: Possible Relationship to Subforms of Cytochrome P‐450

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Abstract
The binding of four sigma receptor ligands,3H‐(+)‐N‐allyl‐N‐normetazocine (3H‐(+)‐SKF 10,047),3H‐(+)‐3‐(3‐hydroxyphenyl)‐N‐(1‐propyl)piperidine (3H‐(+)‐3‐PPP),3H‐haloperidol and3H‐N,N'‐di(o‐totyl)guanidine (3H‐DTG), and the cytochrome P450IID6 ligand and dopamine uptake inhibitor3H‐1‐[2‐(diphenylmethoxy)ethyl]‐4‐(3‐phenylpropyl)piperazine (3H‐GBR 12935) to membranal preparations of rat liver or whole rat brain was examined regarding kinetical properties and inhibition by various compounds with affinity for sigma binding sites or cytochrome P‐450. In rat brain the density of binding sites was increased in order (+)‐SKF 10,047 <(+)‐3‐PPP3H‐(+)‐SKF 10,047 which appears to bind to a homogeneous haloperidol‐sensitive site, there were quite marked differences between the ligands studied, suggesting heterogeneous binding sites. For instance, (+)‐SKF 10,047 and progesterone were potent inhibitors of the binding of3H‐(+)‐SKF 10,047,3H‐(+)‐3‐PPP and3H‐haloperidol but inhibited only a minor fraction of the binding of3H‐DTG to the brain and liver preparations. Multiple binding sites were also indicated by the low Hill coefficients found for most of the compounds studied. It was found that the cytochrome P‐450 inhibitor proadifen (SKF 525A), like haloperidol, was a potent inhibitor of the binding of3H‐(+)‐SKF 10,047,3H‐(+)‐3‐PPP and3H‐haloperidol to the liver and brain preparations, less active in inhibiting the binding of3H‐DTG and least effective on the binding of3H‐GBR 12935. Another cytochrome P‐450 inhibitor, L‐lobeline, was particularly potent in inhibiting the binding of3H‐DTG but was also quite potent inhibitor of the binding of the other sigma ligands. It was less potent in inhibiting the binding of3H‐GBR 12935. The binding of the latter ligand was potently inhibited by the analogous compound GBR 12909 but of the other compounds examined only L‐lobeline, proadifen, haloperidol, DTG and (+)‐3‐PPP had IC50 values below 10 μM. The possibility that the sigma binding sites are identical with some subforms of cytochrome P‐450 is discussed.