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)

A series of newly synthesized 1,5-benzothiazepines derived from diltiazem (CAS 42399-41-7) were tested for calmodulin antagonistic activities using Ca(2+)-calmodulin stimulated phosphodiesterase (PDE). Some compounds possessing the benzoyloxy moieties at position 4 of 1,5-benzothiazepine ring of diltiazem showed a dose-dependent inhibitory action with the potencies comparable to that of a calmodulin antagonist, N-(6-aminohexyl)-5-chloro-1-naphthalene-sulfonamide (W-7). In contrast, diltiazem did not exert the inhibitory action at the same concentrations. Further, radioligand binding experiment, using a radiolabeled 1,5-benzothiazepine, showed that these compounds bound to Ca(2+)-calmodulin complex, but not to calmodulin in the presence of EGTA, suggesting that these 1,5-benzothiazepines are new calmodulin antagonists. Some of these compounds inhibited [3H]diltiazem binding to Ca antagonist binding sites in cell membranes of rat cerebral cortex but with a less potent affinities than diltiazem, suggesting that there was no correlation between their anti-calmodulin effect and the binding affinity to Ca antagonist binding sites. In conclusion, new 1,5-benzothiazepines have been demonstrated to have an anti-calmodulin action. These compounds may possess a pharmacological activity based on their anti-calmodulin action in addition to their interaction with Ca channel.
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PMID:Calmodulin antagonistic action of new 1,5-benzothiazepines derived from diltiazem. 813 75

In the present study the anti-inflammatory activity of the phosphodiesterase inhibitor rolipram (ZK 62,711, CAS 61413-54-5) was tested in a rat model where edema was induced in the ears of the animals by the epicutaneous application of croton oil in ethanol (5%, by volume). The administration of 0.015, 0.15 and 1.5 mg rolipram per ear dose-dependently inhibited the formation of edema. Concomitantly, the body temperature of the rats was decreased. 4-14% of rolipram was percutaneously absorbed within a 5-h interval. The absorbed proportion, represented by the area under the plasma level-time curve, correlated with the inhibition of edema formation and with the decrease in body temperature.
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PMID:Anti-inflammatory activity of rolipram in a rat ear edema model. 814 51

The inotropic and chronotropic actions of toborinone ((+/-)-6-[3-(3,4-dimethoxybenzylamino)-2-hydroxy-propoxy]-2(1H)-qu inolinone CAS 128667-95-8, OPC-18790) in the isolated right atrial and papillary muscles of rabbit and guinea-pig were examined and compared with those of milrinone (CAS 78415-72-2), a pure cyclic GMP-inhibited phosphodiesterase inhibitor. OPC-18790 (10(-7)-10(-4) mol/l) and milrinone (10(-3)-10(-4) mol/l) exerted concentration-dependent increases of contraction in both atrial and papillary muscles isolated from rabbits and guinea-pigs. In the isolated right atrium of rabbits and guinea-pigs, OPC-18790 showed limited increase in heart rate, while milrinone increased heart rate concentration-dependently. OPC-18790 (10(-6) and 10(-5) mol/l in guinea-pigs and 10(-7)-10(-4) mol/l in rabbits) prolonged the action potential duration in the isolated papillary muscles, while milrinone exerted no such change. In whole-cell voltage clamp experiments using isolated cardiac myocytes of guinea-pigs, OPC-18790(10(-5) mol/l) increased the L-type calcium current and inhibited outward potassium currents such as inward rectifying currents and delayed rectifier currents. OPC-18790 and milrinone (10(-6), 3 x 10(-5) mol/l) increased intracellular cyclic AMP levels with an increase in developed tension in isolated right ventricular muscles of guinea-pigs. From the above results, OPC-18790 was shown to be a positive inotropic agent with limited chronotropic effect and electrophysiologically properties different from those of milrinone. It was suggested that the prolongation of action potential duration, which is due to the inhibition of potassium currents, may be involved in OPC-18790's mechanism of positive inotropic action with limited chronotropic effect in addition to the inhibition of cyclic GMP-inhibited phosphodiesterase.
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PMID:Positive inotropic and chronotropic effects of toborinone and its electrophysiological properties in the isolated hearts of rabbits and guinea-pigs. 876 47

(+)-(5-Methyl-6-phenyl)-1,3,5,6-tetrahydro-3,6-methano-1, 5-benzodiazocine-2,4-dione (CAS 165755-40-8, CGP 48506) is a novel Ca2+ sensitizing agent devoid of any other positive inotropic mechanism, particularly phosphodiesterase (PDE) III inhibition. 5-(1-(3,4-Dimethoxybenzoyl)-1,2,3,4-tetrahydroquinolin-6-yl)-6-met hyl-3, 6-dihydro-2H-1,3,4-thiadiazin-2-one (CAS 120223-04-3, EMD 53998) is a PDE III inhibitor with a Ca2+ sensitizing activity residing in its (+)-enantiomer, EMD 57033 (CAS 147527-31-9). In skinned fibres and electrically stimulated left ventricular strips from idiopathic dilated human hearts, New York Heart Association (NYHA) class IV, the Ca2+ sensitizing and inotropic effects of the benzodiazocine CGP 48506 and the thiadiazinones EMD 53998 or EMD 57033 were compared. Both CGP 48506 and EMD 53998 induce a left shift of the Ca2+ activation curve of force towards lower Ca2+ concentrations in skinned fibres, which indicates Ca2+ sensitization. Only EMD 53998, but not CGP 48506, increases skinned fibre force at both minimum (resting) and maximally activating Ca2+ concentrations. This is taken as an argument for a principal difference in the mechanisms of the Ca2+ sensitizing actions of the two compounds. CGP 48506 is shown not to influence the amplitude of the Ca2+ transient in rat cardiomyocytes. On the other hand, both CGP 48506 and EMD 57033 show comparable, though quantitatively different, positive inotropic effects in electrically stimulated left ventricular strip preparations. It is unclear whether the PDE III inhibitory component of the profile of actions of EMD 57033 may play a role in preventing the increase in diastolic tension as expected from the skinned fibre experiments. It is noteworthy that both Ca2+ sensitizing agents act as positive inotropic compounds in the end-stage failing human heart where other inotropic agents like beta 1-adrenergic agonists or PDE inhibitors have been described to fail.
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PMID:Ca2+ sensitization in idiopathic dilated human myocardium. Differential in vitro effects of (+)-(5-methyl-6-phenyl)-1,3,5,6-tetrahydro-3,6-methano-1,5-benzodiazoci ne-2,4-dione, a novel purely Ca2+sensitizing agent, and (+)-5-(1-(3,4-dimethoxybenzoyl)-1,2,3,4-tetrahydroquinolin-6-yl)-6-meth yl-3, 6-dihydro-2H-1,3,4-thiadiazin-2-one on skinned fibres and isolated ventricular strips. 876 48

Endothelial cell contraction plays a pivotal role in vascular leakage. It increases the extravasation of fluid and macromolecules from the lumen into the interstitium. This is also true for bronchial edema. Previous studies have indicated that an elevation of intracellular adenosine-3',5'-cyclic monophosphate (cAMP) or guanosine-3',5'-cyclic monophosphate (cGMP), respectively, can counteract this vascular leakage by improving the endothelial barrier function in analogy to the relaxation of smooth muscle cells. To investigate the potential antiedemateous effects of ularitide acetate (CAS 115966-23-9), isoproterenol hemisulfate (CAS 6078-56-4), sodium nitroprusside (CAS 13755-38-9, SNP), aminophylline (CAS 317-34-0), and combinations of these compounds, their effects on thrombin-induced macromolecular permeability raise in relation to cGMP- or cAMP-levels, respectively, in a model of human umbilical vein endothelial cells (HUVECs) were examined. Ularitide acetate, isoproterenol hemisulfate, and SNP all increased the amount of cyclic nucleotides and decreased the raise in permeability in the following order of potency: isoproterenol hemisulfate > ularitide acetate > SNP. Aminophylline raised both cGMP- and cAMP-levels in a weaker amount and was not able to decrease the thrombin-induced permeability raise on its own. By way of contrast, preincubation of HUVECs with aminophylline resulted in a more than additive potentiation of the cGMP-levels and the permeability lowering induced by ularitide-acetate. These in vitro-data indicate that ularitide-acetate, especially in combination with phosphodiesterase (PDE) inhibitors, could probably have beneficial effects in bronchial permeability edema.
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PMID:Comparison of the effects of ularitide acetate and other bronchorelaxing substances on the thrombin-induced permeability raise of human endothelial cell monolayers. 955 82

Ularitide (CAS 118812-69-4, urodilatin) is a member of the family of the atrial natriuretic peptides. In the present study, the relaxant effects of ularitide acetate, isoproterenol (isoprenaline) hemisulfate, aminophylline, zaprinast, and different combinations between these drugs were investigated on methacholine chloride-precontracted guinea-pig tracheal smooth muscle. Ularitide acetate was a weaker bronchorelaxant than isoproterenol hemisulfate and aminophylline. Moreover the relaxation induced by ularitide acetate was reversible, while the relaxation induced by isoproterenol hemisulfate, aminophylline, and zaprinast was irreversible. Combinations between in each case two of these substances were overadditive, if the phosphodiesterase-inhibiting component was applicated before the combination partner. Their effects were only additive, if the combination partners were applicated simultaneously. All combinations between ularitide acetate and isoproterenol hemisulfate, aminophylline, or zaprinast respectively relaxed the tracheas irreversibly. These results suggest that ularitide acetate might be a novel partner for classical bronchorelaxants in potent bronchorelaxing combinations in the therapy of asthma bronchiale.
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PMID:Synergistic effects of ularitide acetate with classical bronchorelaxants on guinea-pig tracheal smooth muscle. 963 14

Inotropic activity and the effect of CL 86-02-01 (2-(3-methoxy-5-methylsulfinyl-2-thienyl)-1H-imidazo[4,5-c]pyridine hydrochloride, CAS 109 792-24-7) on membrane resting and action potentials were studied in isolated guinea-pig papillary muscles. Membrane resting potential and action potential parameters were not significantly changed, while CL 86-02-01 exerted a concentration-dependent inotropic effect by increasing the maximum rate of force development and maximum rate of force relaxation. Time to peak force, relaxation time and total contraction time were reduced. These effects are similar to those of beta-adrenergic drugs and phosphodiesterase inhibitors, but markedly differ from those described for other positive inotropic agents like cardiac glycosides, calcium agonists, alpha-adrenergic drugs or increased extracellular calcium concentration.
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PMID:Effects of the new imidazopyridine CL 86-02-01 on isolated papillary muscle of guinea-pig hearts. 968 19

The spasmolytic activity of flavoxate (CAS 15301-69-6), anticholinergic agents oxybutynin (CAS 5633-20-5), and trospium chloride (CAS 10405-02-4), drugs commonly utilized in the therapy of hyperactive bladder, and phosphodiesterase (PDE) inhibitors papaverine (CAS 58-74-2) and vinpocetine (CAS 42971-09-5) on muscarinic contractions of detrusor smooth muscle strips isolated from human and porcine urinary bladder was studied in vitro using the organ bath technique. Trospium chloride was most effective in relaxing contractions elicited by muscarinic stimulation, while flavoxate was significantly less effective than all other drugs tested. The relaxing potency of oxybutynin was greater than those of PDE-inhibitors papaverine and vinpocetine but 3,000 fold less significant than those of trospium chloride. The effects of the individual drugs on muscarinic tension of both human and porcine detrusor muscle strips were nearly equal. The present results suggest that the pig might be an appropriate animal model for the study of effects of spasmolytic substances on the contractility of urinary bladder smooth muscle in vitro.
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PMID:Comparison of the effects of various spasmolytic drugs on isolated human and porcine detrusor smooth muscle. 974 13

Toborinone ((+/-)-6-[3-(3,4-dimethoxybenzylamino)-2-hydroxypropoxy]-2(1H)-qui nolinone, CAS 128667-95-8, OPC-18790), a novel cardiotonic agent with an inhibitory action on phosphodiesterase, is known to have a potent positive inotropic action with no positive chronotropic effect. The effectiveness of this drug in the treatment of heart failure occurring immediately after extracorporeal circulation (ECC) in cardiac surgery was investigated. The study was conducted in 12 patients with valvular heart disease showing a cardiac index (CI) of below 2.8 l/min/m2 and/or pulmonary capillary wedge pressure (PCWP) or pulmonary arterial diastolic pressure (PAD) of above 8 mmHg immediately after extracorporeal circulation. In group A (n = 6), toborinone was infused at a rate of 40 micrograms/kg/min for the first 5 min and then at 10 micrograms/kg/min for 85 min. In group B (n = 6), the drug was infused at a rate of 10 micrograms/kg/min for the entire 90 min. CI, mean systemic arterial pressure (mSAP), mean pulmonary artery pressure (mPAP), CVP, PCWP, and heart rate were measured at 5, 15, 30, 60, and 90 min after the start of infusion. The infusion volume required to maintain a constant PCWP was also estimated. In group A, CI increased rapidly and significantly from the baseline of 2.48 +/- 0.23 l/min/m2 to 3.57 +/- 1.07 l/min/m2 at 5 min after the start of infusion, and at that time mSAP was slightly decreased. In group B, CI increased gradually from the baseline of 2.53 +/- 0.18 l/min/m2 to 3.08 +/- 0.34 l/min/m2 at 15 min after the start of infusion, but almost no change was seen in mSAP. During the first 30 min, group A required a significantly larger infusion volume (983 +/- 395 ml) than group B (475 +/- 184 ml). From 30 to 90 min after the start of infusion, CI remained increased to similar levels in both groups and mSAP levels were also similar. There were no significant differences between the two groups in any other parameter. Continuous infusion of toborinone appears to be effective for treating heart failure occurring immediately after ECC in cardiac surgery. Initial loading at a rate of 40 micrograms/kg/min rapidly increased CI but was accompanied by mild hypotension. Constant infusion at 10 micrograms/kg/min brought about a more gradual effect that was similar to that of loading at 40 micrograms/kg/min, but without inducing hypotension. Thus, infusion at 10 micrograms/kg/min is considered preferable in order to avoid a larger-than-necessary infusion volume.
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PMID:Study on the effectiveness of toborinone (OPC-18790) in the treatment of heart failure in patients following cardiac surgery. 1041 65

The effect of 1-cyclopentyl-3-ethyl-6-(3-ethoxypyrid-4-yl)- 1H-pyrazolo[3,4-d]pyrimidin-4-one (SR 265579), a potent inhibitor of guanosine 3',5'-cyclic monophosphate (cyclic GMP) phosphodiesterase (PDE5), was examined regarding its specificity toward the other cyclic nucleotide phosphodiesterases, the effect on cyclic nucleotide levels and the bronchodilatory activity, both in vitro and in vivo in guinea-pigs. The effects were compared to those obtained with zaprinast (CAS 37762-06-4), a known PDE5 inhibitor. Anion-exchange chromatography of the soluble fraction of guinea-pig homogenates revealed 5 peaks which corresponded to PDE1, PDE2, PDE3, PDE4 and PDE5. SR 265579 produced a potent and competitive inhibition, with respect to cyclic GMP, of PDE5 with a Ki of 6.4 nmol/l. The compound was 25 fold more potent than zaprinast and demonstrated selectivity toward PDE5. The selectivity index was 14 and 33 with respect to PDE4 and 3, respectively. PDE1 and 2 were only inhibited at considerably higher concentrations. SR 265579 specifically increased the intracellular cyclic GMP levels in guinea-pig tracheal epithelial cells (EC50 = 117 nmol/l). Moreover, in the guinea pig, plasma cyclic GMP levels were significantly increased after the intravenous or oral administration of doses as low as 1 mg/kg. Isolated guinea-pig trachea were relaxed by the addition of SR 265579 as evaluated by measuring either spontaneous tone or relaxation of histamine and acetylcholine-precontracted preparations. PD2 values were of 7.64, 6.52 and 5.25, respectively. In vivo, after i.v. administration, bronchodilatory activity was demonstrated in an artificially-ventilated guinea-pig histamine-induced bronchospasm model with an ED50 of 0.63 mg/kg. In all experiments, SR-265579 was proved to be more active than zaprinast. These results demonstrate that SR 265579 is an orally active, potent and specific inhibitor of PDE5.
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PMID:Experimental studies on guanosine 3',5'-cyclic monophosphate levels and airway responsiveness of the novel phosphodiesterase type 5 inhibitor SR 265579 in guinea-pigs. 1048 15


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