SKF 525-A and cytochrome P-450 ligands inhibit with high affinity the binding of [ 3H]dextromethorpan and σ ligands to guinea pig brain.

Abstract

The DM 1 σ 1 site binds dextromethorphan (DM) and σ receptor ligands. The broad binding specificity of this site and its peculiar subcellular distribution prompted us to explore the possibility that this site is a member of the cytochrome P-450 superfamily of enzymes. We tested the effects of the liver microsomal monooxygenase inhibitor SKF 525-A (Proadifen), and other P-450 substrates on the binding of [ 3H]dextromethorphan, [ 3H]3-(-3-Hydroxyphenyl)-N-(1-propyl) piperidine and (+)-[ 3H]1,3-Di-o-tolylguanidine ([ 3H]DTG) to the guinea pig brain. SKF 525-A, 1-lobeline and GBR-12909 inhibited the binding of the three labeled ligands with nM affinity. Each drug has identical nM Ki values for the high-affinity site labeled by the three ligands. This indicated that they displaced the labeled ligands from the common DM 1 σ 1 site. Debrisoquine and sparteine, prototypical substrates for liver debrisoquine 4-hydroxylase, displayed Ki values of 9–13 and 3–4 μM respectively against the three labeled ligands. These results, the broad specificity of the DM 1 σ 1 binding site, and its peculiar subcellular distribution, raises the possibility that this binding site is a member of the cytochrome P-450 superfamily of isozymes, rather than a neurotransmitter receptor. These findings may have important implications for the understanding of the therapeutic, side effects and toxicity of several neurotropic drugs.