Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.1.4.1 (phosphodiesterase)
18,767 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

With a view of decoding the mechanisms of their action the effect of papaverine, chlorpromazine and imipramine produced on a number of blood platelets hemostatic functions was studied. All the three drugs suppress in a characteristic fashion the aggregation on blood platelets caused by thrombin in the Tyrode solution and in a plasma defibrilated by heating, as well as by collogen and ADP in the citrated plasma. Unlike chlorpromazine and imipramine papaverine exerts a strong inhibiting action on the phosphodiesterase activity. Chlorpromazine and imipramine suppress the absorption of serotonin and retraction more intensively than this is done by papaverine and call forth morphological changes in the blood platelets that proceed parallel with changes in the intensity of the photodiffusion and liberation of endogenous serotonin. It is postulated that chlorpromazine and imipramine manifest their inhibitory effect through nonspecific damage of the blood platelets membranes, whereas papaverine does this through exchange of adenine-nucleotides and, especially, of 3',5'-AMP.
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PMID:[Comparative effect of chlorpromazine, imipramine and papaverine on the blood platelet function]. 19 25

Chlorpromazine (5 x 10(-3) M) administered to Dictyostelium discoideum cells inhibited its growth and morphogenesis. Cells treated with chlorpromazine were found to have distorted morphology. At lower doses of chlorpromazine the development was delayed. Early developmental events such as cell streaming, cell aggregations, development of EDTA stable cell contacts, cAMP-chemotaxis etc, were inhibited. Chlorpromazine was also found to inhibit spore formation. Culturing D. discoideum cells on chlorpromazine agar, in supernatant taken from the chlorpromazine treated cells, or co-culturing of chlorpromazine-treated and control cells, inhibited the development of normal Dictyostelium cells. Chlorpromazine-treated cells showed a higher cAMP-dependent extracellular phosphodiesterase activity.
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PMID:Effects of chlorpromazine on growth and development of Dictyostelium discoideum. 166 85

Long-term amiodarone therapy is invariably associated with some side effects. Although its mechanism of action, as an antiarrhythmic drug is well understood, the side effect profile of amiodarone is not yet established. To determine possible mechanisms, the interaction of amiodarone and its major metabolite desethylamiodarone with calmodulin was investigated, since calmodulin is known to regulate Ca2+ transport, cell proliferation and the enzymes involved in signal transduction and nucleotide metabolism. The interaction between the drugs and calmodulin was studied by monitoring intrinsic tyrosine fluorescence of calmodulin and by using a fluorescent probe, N-phenyl-1-naphthylamine (NPN). 14C-Chlorpromazine displacement studies were conducted to differentiate the specific binding sites. The effect on the biological activity of calmodulin was determined with calmodulin dependent phosphodiesterase and Ca2(+)-ATPase. The dansyl calmodulin was used as fluorescent probe to study the effect of these drugs on complex formation between calmodulin and phosphodiesterase. Both amiodarone and desethylamiodarone decreased tyrosine fluorescence of calmodulin with IC50 of 4.9 and 4.4 microM respectively and these interactions were Ca2(+)-dependent. NPN fluorescence was also affected in a concentration dependent manner. These drugs also displaced bound 14C-chlorpromazine from calmodulin and the effect was biphasic. However, desethylamiodarone was more potent than amiodarone. The binding of 3H-amiodarone to calmodulin was modified by a variety of compounds, one class of compounds decreased and the other increased 3H-amiodarone binding to calmodulin. Only, desethylamiodarone inhibited the phosphodiesterase activation by calmodulin with IC50 of 13.2 microM without changing the basal enzyme.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Modulation of calmodulin properties by amiodarone and its major metabolite desethylamiodarone. 184 30

Upon irradiation with UV light, chlorpromazine binds irreversibly to calmodulin and inactivates it. To determine whether this chlorpromazine-calmodulin (CPZ-CaM) complex can inhibit the actions of native calmodulin, we examined its effects on the activity of calmodulin-sensitive cyclic nucleotide phosphodiesterase from rat brain and on the Ca++-adenosine triphosphatase (ATPase) of human erythrocyte membranes. The CPZ-CaM complex was prepared by irradiating purified bovine brain calmodulin in the presence of chlorpromazine and Ca++. The sample was then dialyzed extensively to remove reversibly bound chlorpromazine and then assayed for its ability to activate calmodulin-sensitive phosphodiesterase and Ca++-ATPase, and for its ability to block the stimulatory effects of native calmodulin on these enzymes. The CPZ-CaM complex had no effect on the basal activity of either enzyme; it neither activated nor inhibited the enzymes when assayed in the absence of calmodulin. However, it affected differentially the activation of the two enzymes by native calmodulin. The CPZ-CaM complex totally inhibited calmodulin-stimulated phosphodiesterase but had no effect on the activation of the ATPase by calmodulin. Other studies showed that CPZ-CaM increased the activation constant (Ka) for the interaction of calmodulin with phosphodiesterase but did not affect the maximal activation (Vmax) of the enzyme by calmodulin. Neither calmodulin nor CPZ-CaM altered the Km for the interaction between phosphodiesterase and cyclic AMP. These results suggest that CPZ-CaM inhibits the calmodulin-induced activation of phosphodiesterase by competing with calmodulin for regulatory sites on the enzyme and not by interacting with calmodulin itself or by blocking the interaction of cyclic AMP with the enzyme.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Differential inhibition of calmodulin-sensitive phosphodiesterase and Ca++-adenosine triphosphatase by chlorpromazine-linked calmodulin. 282 96

1. Chlorpromazine (CPZ) is a unique molecule which has many potential sites of action, as well as a propensity to be transformed into a host of metabolites possessing varying degrees of pharmacological and/or toxic reactions. This investigation examined the rank order of potency of CPZ and eight metabolic derivatives with respect to displacement of 3H-spiperone at central dopamine-2 (DA-2) receptors, 3H-pirenzepine at central muscarinic-1 (M-1) receptors, and inhibition of calmodulin-induced activation of cyclic AMP-dependent phosphodiesterase. 2. The most potent CPZ analogues to displace labelled spiperone from DA-2 receptors in rat striatum were: 3-hydroxy-CPZ, CPZ, 3,7-dihydroxy-CPZ, and 7-hydroxy-CPZ. Intermediate potency was observed with 8-hydroxy-CPZ, 3,7,8-trihydroxy-CPZ, and 7,8-dihydroxy-CPZ. Chlorpromazine sulphoxide and 7,8-dimethoxy-CPZ displayed the least activity at DA-2 receptors. 3. Displacement of labelled pirenzepine from M-1 receptors in rat frontal cortex occurred to the greatest extent with CPZ which was one to two orders of magnitude more potent than noted for 3-hydroxy-CPZ greater than 7-hydroxy-CPZ greater than CPZ-sulphoxide greater than 8-hydroxy-CPZ greater than 7,8-dimethoxy-CPZ. The least potent agents were 3,7-and 7,8-dihydroxy-CPZs and 3,7,8-trihydroxy-CPZ. 4. A partially purified calmodulin-sensitive preparation of cyclic AMP-dependent phosphodiesterase from guinea pig heart was most sensitive to inhibition by 7,8-dihydroxy-CPZ, 7,8-dimethoxy-CPZ, 3-hydroxy-CPZ, 7-hydroxy-CPZ, 8-hydroxy-CPZ and CPZ. Least inhibition occurred with 3,7-dihydroxy-CPZ, 3,7,8-trihydroxy-CPZ and CPZ-sulphoxide. 5. The DA-2 receptors were more sensitive to the active CPZ analogues than were the M-1 receptors while calmodulin-activated phosphodiesterase was the least sensitive preparation. 6. Comparisons of data were made with existing information from other laboratories and in general CPZ, 7-hydroxy-CPZ and 3-hydroxy-CPZ were the most potent compounds across different test conditions.
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PMID:Correlation of activity of chlorpromazine and respective hydroxy, dimethoxy and sulphoxide analogues on dopamine, muscarinic, histamine and calmodulin sites of action. 283 73

Two chlorpromazine analogs, 7,8-diOH- and 7,8-dioxo-didesmethyl-chlorpromazine were compared to chlorpromazine (CPZ) with regard to inhibition of three parameters of enzyme activity in rat striatum: 1) dopamine + GTP-sensitive adenylate cyclase in homogenates; 2) dopamine, GTP, calmodulin and Ca++-sensitive adenylate cyclase in washed particulate fractions; and 3) calmodulin-Ca++ activation of high Km cyclic AMP dependent phosphodiesterase in dialyzed supernatant fractions. Chlorpromazine was clearly the most potent antagonist in all three experimental conditions. The CPZ derivatives displayed greatest potency on the particulate adenylate cyclase and all three drugs were 1 to 2 orders of magnitude more effective as inhibitors of the adenylate cyclase preparations than with the calmodulin-Ca++ phosphodiesterase.
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PMID:Comparison of inhibitory actions of chlorpromazine or its 7,8-dihydroxy and 7,8-dioxo-didesmethyl analogs on DA-sensitive adenylate cyclase and calmodulin activation of phosphodiesterase in rat striatum. 298 71

Chlorpromazine (CPZ) at dosages of 10 mg/kg body weight (b.wt.) affected the cytochemical localization of cAMP-dependent phosphodiesterase (cAMP PDE) activity in the synapses of the rat frontal cortex. Postsynaptic cAMP PDE activity was inhibited, and presynaptic activity increased. CPZ also inhibited membrane-bound ATPase activity in the frontal cortex. The activity of Na+-K+-ATPase was significantly (P less than 0.005) inhibited in isolated plasma membranes from the rat frontal cortex. CPZ exposure also affected the cytochemical localization of cations with potassium pyroantimonate. Precipitate, which could be removed with 5 mm EGTA, was decreased in the mitochondria and synaptic vesicles in presynaptic areas after CPZ treatment. The incorporation of 45Ca2+ into slices of the rat frontal cortex was also significantly (P less than 0.001) inhibited by CPZ. This ultrastructural study shows that CPZ may affect biochemical events in an opposite manner in the pre- and post-synaptic areas of some neurons of the frontal cortex.
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PMID:Effect of chlorpromazine on the localization of cAMP phosphodiesterase. 299 Jan 46

Treatment of Chinese hamster ovary cells with dansylcadaverine or N-(6-aminohexyl)-5-chloro-1-naphthylenesulfonamide (W7) reduced cell attachment in a reversible, dose-dependent manner. The concentration of dansylcadaverine required to produce 50% inhibition of adhesion was significantly higher than that of W7, 300 microM and 50 microM, respectively. Concentrations of dansylcadaverine and W7 which produced decreased adhesion also antagonized calmodulin-dependent activation of phosphodiesterase. Chlorpromazine, another calmoldulin antagonist also decreased cell attachment. Dansylcadaverine and W7 both interfere with cellular transglutaminase activity, but several other transglutaminase antagonists, such as methylamine, butylamine, putrescine and bacitracin, had no effect on CHO cell attachment. We conclude that naphthylsulfonamides such as dansylcadaverine and W7 may inhibit the attachment of CHO cells by a mechanism which could involve inhibition of calmodulin-dependent processes, although further studies are required to show a direct role of calmodulin in cell adhesion.
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PMID:Inhibition of the adhesion of Chinese hamster ovary cells by the naphthylsulfonamides dansylcadaverine and N-(6-aminohexyl)-5-chloro-1-naphthylenesulfonamide (W7). 613 61

A series of Benzo [b]-promazines and analino-N, N-dimethylpropylamine analogs and the free radical of chlorpromazine were compared to chlorpromazine and promazine in the rat striatum for their ability to inhibit either dopamine activated adenylate cyclase or calmodulin stimulation of a partially purified high Km cyclic AMP phosphodiesterase. Chlorpromazine and the corresponding free radical were generally the most potent inhibitors of the two enzyme preparations, however, Piperazino-Benzo [b]-promazine, 1-Oxo-Benzo [b]-promazine, N-38-76-3A and Benzo [b]-promazine were relatively effective inhibitors. To a lesser extent, tyrosine, N-57-77, Piperidino-Benzo [b]-promazine, Diethyl-Benzo [b]-promazine, promazine and 1-Oxo-Diethyl-Benzo [b]-promazine exerted varying degrees of antagonism of the two enzymes. In all instances the compounds inhibited dopamine-sensitive adenylate cyclase to a greater extent than the calmodulin activated phosphodiesterase.
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PMID:Benzo [b]-promazines, chlorpromazine free radical and analino-N, N-dimethylpropylamine analogs influence rat striatal DA-adenylate cyclase and calmodulin-phosphodiesterase. 628 52

Cyclic AMP and the isozyme families that control its concentration have an important role in rat mast cells. We have attempted to determine the total phosphodiesterase activity in rat mast cells by means of specific and non-specific inhibitors of phosphodiesterases. We used a fluorescent analogue of cAMP, 2'-O-anthraniloyl cAMP, the fluorescence intensity of which decreases when hydrolysed by phosphadiesterase (PDE), providing a measurement of total activity of PDE. The PDE inhibitors produced a decrease in the fluorescence fall. Therefore, we can establish that at least Type I, III, IV and probably Type V PDE are present in rat mast cells. We have also studied the effect of these PDE inhibitors on histamine release elicited by compound 48/80 and sodium fluoride. Chlorpromazine, a Type I PDE inhibitor, only slightly inhibits the fluoride-evoked response, while, on the other hand, milrinone, a Type III PDE inhibitor, does not modify the response to compound 48/80.
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PMID:Determination of phosphodiesterase activity in rat mast cells using the fluorescent cAMP analogue anthraniloyl cAMP. 856 12


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