Receptors for diphenylbutylpiperidine neuroleptics in brain, cardiac, and smooth muscle membranes. Relationship with receptors for 1,4-dihydropyridines and phenylalkylamines and with Ca 2+ channel blockade

Abstract

Neuroleptic molecules of the diphenylbutylpiperidine series (DPBP), such as fluspirilene, penfluridol, pimozide and clopimozide, antagonize binding of (−)[ 3H]desmethoxyverapamil ((−)[ 3H]D888) and (+)[ 3H]PN 200-110 to rabbit brain, heart and smooth muscle membranes. The diphenylbutylpiperidine binding site in all these tissues is distinct but is allosterically related to the 1,4-dihydropyridine binding site and to the binding site. High and low affinity binding sites for (−)D888 were identified. (−)[ 3H]D888 binding at both types of sites was inhibited following the saturation of a single type of diphenylbutylpiperidine binding site. Half-maximal inhibition (K 0.5) of brain, heart and smooth muscle membranes binding by different diphenylbutylpiperidines was in the range of 10–100 nM. These K 0.5 values were one to two orders of magnitude higher than those found for the high affinity diphenylbutylpiperidine receptor in skeletal muscle membranes. The K 0.5 values found in binding experiments in smooth muscle were similar to the (IC 50) values for half-maximal inhibition by diphenylbutylpiperidine of voltage-dependent 45Ca 2+ influx through the slow Ca 2+ channel.