RT Journal Article
SR Electronic
T1 Mechanism by Which Psychotropic Drugs Inhibit Adenosine Cyclic 3',5'-Monophosphate Phosphodiesterase of Brain
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP 581
OP 589
VO 12
IS 4
A1 LEVIN, ROBERT M.
A1 WEISS, BENJAMIN
YR 1976
UL http://molpharm.aspetjournals.org/content/12/4/581.abstract
AB 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(β-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.