Binding affinity and antimuscarinic activity of sigma and phencyclidine receptor ligands.

The characterization of the sigma receptor has been hampered by the lack of a functional bioassay system. Drugs that bind to sigma receptors have been reported to inhibit carbachol-induced phosphatidylinositol turnover in rat brain; however, these drugs might directly affect muscarinic acetylcholine receptors. The purpose of the present study was to determine the affinity for muscarinic receptors and the antimuscarinic activity of sigma and phencyclidine receptor ligands. All of the drugs tested inhibited the binding of [3H]N-methylscopolamine to guinea pig cerebral cortical membranes with KI values in the micromolar range and also inhibited carbachol-induced contractions in the guinea pig ileum. These results demonstrate that these compounds have substantial antimuscarinic activity which might limit the use of the inhibition of carbachol-induced phosphatidylinositol turnover as a functional assay system for studying sigma ligands. Furthermore, this antimuscarinic activity must be considered when evaluating the effects of these compounds after in vivo administration.