Sites of action of phencyclidine. III. Interactions with muscarinic receptors

The effects of phencyclidine (PCP) and phencyclidine methiodide (PCP-MeI) on contractions of longitudinal muscle of guinea pig ileum and specific binding of [ ³H](DL)3-quinuclidinyl benzilate ([ ³H]QNB) to muscarinic receptors in these muscles and rat brain were studied. PCP inhibited competitively muscarinic agonist-induced contractions of the longitudinal muscle of guinea pig ileum at concentrations below 10 μM (K(i)= 0.45 μM). However, at 50 μM noncompetitive blockade of contraction was seen. In contrast, PCP-MeI inhibited ileum contractions competitively at concentrations of up to 100 μM (K(i)= 0.2 μM). Both drugs inhibited binding of [ ³H]QNB to muscarinic acetylcholine (ACh) receptors of rat cerebral cortex and brain stem and to ileal longitudinal muscle (apparent K(i)'s of from 0.8 to 3.7 μM). There was no evidence of noncompetitive receptor binding inhibition at PCP concentrations which produced noncompetitive inhibition of smooth muscle contraction. There were no indications of multiple receptor populations, cooperative interactions, or receptor isomerization with either drug. PCP-MeI was slightly more potent in its competitive muscarinic actions than PCP. Although the dissociation constant (K(d)) of PCP from muscarinic receptors in brain cortex was significantly lower than in brain stem, the K(d) values for PCP-MeI were the same. Treatment with N-ethylmaleimide did not affect the inhibition of [ ³H]QNB binding to muscarinic receptors by PCP. Based on several characteristics of the inhibition by PCP and PCP-MeI of [ ³H]QNB binding to rat brain muscarinic receptors and their inhibition of the contractions of longitudinal muscle of guinea pig ileum, PCP and PCP-MeI are considered antagonists of muscarinic receptors in rat brain.