Molecular Pharmacology, Vol 16, 1089-1094, Copyright © 1979 by the American Society for Pharmacology and Experimental Therapeutics

Inhibition of Calcium-Dependent Regulator-Stimulated Phosphodiesterase Activity by Neuroleptic Drugs Is Unrelated to Their Clinical Efficacy

¹ Friedrich Miescher-Institut, P.O. Box 273, CH-4002 Basel, Switzerland
² Physics Department, Central Function Research, Ciba-Geigy Limited, CH-4002 Basel, Switzerland

It has previously been suggested that some of the pharmacological and therapeutic effects of certain neuroleptic drugs depend upon their ability to inhibit calcium-dependent regulator-(CDR)-stimulated phosphodiesterase activity. To further test this hypothesis, clinically active and inactive isomers of a number of neuroleptics were examined as CDR inhibitors. Both active and inactive isomers of all the drugs investigated were equally inhibitory in this assay. The IC₅₀ values for CDR inhibition obtained for these and other neuroleptics correlated well with their octanol:water partition coefficients. It is concluded, therefore, that the inhibitory effects of these drugs on the CDR protein are unrelated to their clinical efficacy and may be due to nonstereospecific hydrophobic interactions with the CDR protein.

Note:
ACKNOWLEDGMENTS The authors gratefully acknowledge the gifts of drugs from Merck, Sharp and Dohme, Lundbeck, Wander, Janssen, Ayerst and Delagrange. We also thank Mr. K. Jäkel for his excellent technical assistance and Drs. L. Maître and M. Staehelin for helpful discussions.