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Levin RM, Weiss B.
“Mechanism by Which Psychotropic Drugs Inhibit Adenosine Cyclic 3',5'-Monophosphate Phosphodiesterase of Brain”.
Mol. Pharmacol.. 1976;12(4):581-89.
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Abstract
Inhibition of brain cAMP phosphodiesterase (PD) by psychotropic drugs was studied. Methods 2 Sources of PD were used: a partially purified, soluble activator deficient PD from bovine brain and a highly purified PD separated from rat brain (Sprague-Dawley) by polyacrylamide gel electrophoresis. PD activity was measured by the luciferin luciferase method. Activator was purified from bovine brain by a previously reported method. Results Chlorpromazine (CPZ, SK+F) selectively inhibited the activation of bovine PD by activator (10 U). Iso was 42 yM. CPZ did not inhibit PD activity in the absence of activator. EGTA (0.3 naM) specifically inhibited PD activation. CPZ and EGTA mechanisms were different since EGTA chelated calcium and its PD inhibition could be overcome by increasing CaZ+ but not activator concentration. CPZ (50 11M) inhibition of PD, however, could be overcome by increasing the activator but not the Ca2+ concentration. Kinetic analysis revealed that CPZ was a competitive PD inhibitor. Similar effects were obtained with trifluoperazine (TF) on the highly activatable form of PD purified from rat cerebrum. CPZ was about 3x more effective in blocking cAMP PD (15045 mcM) than cyclic GMP PD activation (150 = 40 mcM). The I50 values (mcM) of bovine PD (activated and unactivated, respectively) using 400 11M cAMP as substrate were: TF, 10,>300; thioridazine (Sandoz), 18, >1000; CPZ,42, >500; CPZ sulfoxide, 2500, 7500; promethazine (Wyeth), 340, >.1000; chlorprothixene (Roche), 16, >2000: benperidol (Janssen), 58, >300 pimozide (McNeil), 7, >100; medazepam 150, > 1000; chlordiazopaxide, 320, 2500' amitriptyline (Merck-USA) 130, >1000; protriptyline, 200, >1000; desipramine (Merrel9, 125, >1000; the ophylline, 1500, 2500 papaverine; 130, 210; amphetamine > 10 mM, 10 mM; mescaline > 5 mM, > 5 m. pentylenetetrazol, > 10 mM, >10 mM; D-LSD,>2.5 mM, :>2 5 mM; pipradol, >1 mM >1 mM; azacyclonol, >1 mM, >1 mM; pentobarbital, >10 mM, >10 mM and morphine, >4 mM, >4 mM.
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