Molecular Pharmacology, Vol 12, 581-589, Copyright © 1976 by the American Society for Pharmacology and Experimental Therapeutics

Mechanism by Which Psychotropic Drugs Inhibit Adenosine Cyclic 3',5'-Monophosphate Phosphodiesterase of Brain

¹ Department of Pharmacology, Medical College of Pennsylvania, Philadelphia, Pennsylvania 19129

Bovine brain contains several molecular forms of adenosine cyclic 3',5'-monophosphate phosphodiesterase. The activity of one of these forms is increased several fold by an endogenous protein activator. Chlorpromazine, a potent phenothiazine tranquilizer, specifically inhibits the activation of a partially purified phosphodiesterase prepared from bovine brain at concentrations which do not inhibit the enzyme in the absence of activator. Ethylene glycol bis(-aminoethyl ether)-N,N'-tetraacetic acid (EGTA), a calcium chelator, also specifically inhibits the activation of phosphodiesterase. However, the mechanisms by which EGTA and chlorpromazine act are different. EGTA produces its effect by chelating calcium, a required cofactor for phosphodiesterase activation; the EGTA-induced inhibition can be overcome by increasing the calcium concentration but not by increasing the concentration of activator. In contrast, chlorpromazine inhibits the activation of phosphodiesterase by interfering with the phosphodiesterase-activator interaction; the chlorpromazine-induced inhibition can be overcome by increasing the concentration of activator but not by increasing the concentration of calcium. Several other psychotropic drugs also inhibit the activation of phosphodiesterase of bovine brain. The antipsychotic agents trifluoperazine, thioridazine, benperidol, pimozide, and chlorprothixene are all potent, selective inhibitors of the activation of phosphodiesterase. The antianxiety agents medazepam and chlordiazepoxide and the antidepressants amitriptyline, protriptyline, and desipramine also selectively inhibit the activation of phosphodiesterase but are significantly less potent than the antipsychotics. Phenothiazines with relatively weak antipsychotic actions, chlorpromazine sulfoxide and promethazine, are less selective and less potent inhibitors than the antipsychotic phenothiazine derivatives. Other agents having central pharmacological actions, such as pentobarbital, pipradrol, D-lysergic acid diethylamide, pentylenetetrazol, morphine, and amphetamine, are poor inhibitors of either the activated or unactivated phoshodiesterase. These findings suggest that (a) the mechanism by which the phenothiazines inhibit the activation of phosphodiesterase involves competition with the endogenous protein activator of phosphodiesterase, and (b) selective inhibition of the activation of phosphodiesterase is a property common to agents which are effective in certain forms of psychiatric illnesses rather than to either general central nervous system depressants or stimulants.

This article has been cited by other articles:

				H. Patel, S. S. Margossian, and P. D. Chantler Locking Regulatory Myosin in the Off-state with Trifluoperazine J. Biol. Chem., February 18, 2000; 275(7): 4880 - 4888. [Abstract] [Full Text] [PDF]

				M. A. Garcia and S. Meizel Progesterone-Mediated Calcium Influx and Acrosome Reaction of Human Spermatozoa: Pharmacological Investigation of T-Type Calcium Channels Biol Reprod, January 1, 1999; 60(1): 102 - 109. [Abstract] [Full Text]

				P. M. Jones and S. J. Persaud Protein Kinases, Protein Phosphorylation, and the Regulation of Insulin Secretion from Pancreatic {beta}-Cells. Endocr. Rev., August 1, 1998; 19(4): 429 - 461. [Abstract] [Full Text] [PDF]

				T. J. TORPHY Phosphodiesterase Isozymes . Molecular Targets for Novel Antiasthma Agents Am. J. Respir. Crit. Care Med., February 1, 1997; 157(2): 351 - 370. [Full Text]

				L. S. Wright, P. J. Bertics, and F. L. Siegel Calmodulin N-Methyltransferase. KINETICS, MECHANISM, AND INHIBITORS J. Biol. Chem., May 31, 1996; 271(22): 12737 - 12743. [Abstract] [Full Text] [PDF]

				E. Schweitzer, M. Sanderson, and C. Wasterlain Inhibition of regulated catecholamine secretion from PC12 cells by the Ca2+/calmodulin kinase II inhibitor KN-62 J. Cell Sci., January 7, 1995; 108(7): 2619 - 2628. [Abstract] [PDF]

				W. Cheung Calmodulin plays a pivotal role in cellular regulation Science, January 4, 1980; 207(4426): 19 - 27. [Abstract] [PDF]