Phosphodiesterase inhibition

4-Dimethylimidazo[l,5-a]quinoxalines 189, containing different substituents in the 1-, 6- and 8-positions, and above-mentioned imidazo[l,5-a]quinoxalines 188 are lOA phosphodiesterase (PDEIOA) inhibitors and can be used for designing antischizophrenia drugs (Malamas et al. 2010, 2011b). 

The presence of the pyrrolidine, morpholine, cyclohexane, piperidine, or aza-cycloheptane moiety in the 1-position of imidazo[l,5-a]quinoxalin -ones, along with amide groups in the 7(8)-position, leads to inhibition of phosphodiesterase 9 (PDE9) therefore, such compounds are used for developing dmgs that eliminate urination disorders (Okada et al. 2009 Kaizawa et al. 2011). 

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Kenakin, T. P., and Scott, D. L. (1987). A method to assess concomitant cardiac phosphodiesterase inhibition and positive inotropy. J. Cardiovasc. Pharmacol. 10 658—666. 

Quinazolines containing an electron-rich carbocyclic ring have been associated with smooth muscle relaxant activity. The mechanism of action (phosphodiesterase inhibition, a- adrenergic blockade) and organ selectivity (bronchi, vascular smooth muscle) vary greatly with substitution on the heterocyclic ring. 

There are a variety of structural classes of compounds that are active against each phosphodiesterase, and evidence suggests that selective inhibitors of PDEs can be identified. The structural diversity of PDE inhibitors provides a multitude of opportunities for development of compounds with drug-like properties. Furthermore, phosphodiesterase inhibition, which avoids direct interaction of a compound with a cell surface or nuclear receptor, may circumvent some of the target selectivity issues that can complicate receptor-based therapeutic approaches. As noted above, the specific subcellular distribution of phosphodiesterase enzymes is a key feature of their ability to modulate intracellular signaling pathways. This localization of the enzyme may minimize non-specific target... 

Dipyridamole is a platelet adhesion inhibitor, although the mechanism of action has not been fully elucidated. The mechanism may relate to 1) Inhibition of red blood cell uptake of adenosine, itself an inhibitor of platelet reactivity, 2) phosphodiesterase inhibition leading to increased cyclic-3 , 5 -adenosine monophosphate within platelets and, 3) inhibition of thromboxane A2 formation,... 

Phosphodiesterase inhibition. Hot water extract of the rhizome, at a concentration of 1 mg/mL, was inactive . 

Theophylline Uncertain phosphodiesterase inhibition t adenosine receptor antagonist Bronchodilation, cardiac stimulation, increased skeletal muscle strength (diaphragm) Asthma, COPD Oral duration 8-12 h but extended-release preparations often used Toxicity. Multiple (see text)... 

Ketotifen is a nonspecific, oral, mast cell stabilizer introduced in 1972 (1). The prominent biochemical-pharmacological activities of ketotifen are H,-receptor antagonism, phosphodiesterase inhibition, inhibition of the formation SRS-A, and inhibition of calcium flux in smooth muscle preparations all these actions are suited to prevent a development of asthmatic conditions. Promising results were obtained in early clinical trials ketotifen was equipotent with disodium cromoglycate in prevention of asthma induced by spontaneous excer-cise or by antigens. Also, ketotifen is more specific than clemastine as a H-,-receptor antagonist. However, more recent, controled trials failed to substantiate the early therapeutic optimism. The beneficial effect of ketotifen in the treatment of asthma is only small it was noted that this effect is associated with pronounced sedation (2). 

Katz SD. Potential role of type 5 phosphodiesterase inhibition in the treatment of congestive heart failure. Congest Heart Fail 2003 9 9-1 5. 

Muscarinic antagonists, such as ipratropium, are also administered by inhalation. They antagonize the parasympathetic bronchoconstriction which may be present in some patients with chronic obstructive lung disease. Methylxanthines, such as theophylline and aminophylline, which are not administered by inhalation, relax bronchial muscle, possibly via phosphodiesterase inhibition. 

Inhibition of l-phosphatidylinositol-4,5-biphosphate phosphodiesterase Inhibition of translation Inhibition of DNA topoisomerase... 

The spasmolytic action of cyclandelate, an ester of man-delic acid, was described as early as 1959, but only in later years have its properties been more fully investigated. It appears to act as a calcium channel blocker in smooth muscle and platelets, this effect being partly dne to inhibition of phosphodiesterases. It also produces increased deformability of erythrocytes, the mechanism of which is so far unknown, although phosphodiesterase inhibition may again be responsible. Cyclandelate also rednces the activity of the rate-limiting enzyme in the biosynthesis of cholesterol (HMG-CoA), and its antidiabetic properties may be due to inhibition of aldose rednctase. 

AminophyUme facilitates neuromuscular transmission, perhaps by increasing neurotransmitter release, through raising cyclic AMP concentrations at the neuromuscular junction via phosphodiesterase inhibition (37). This would account for the antagonism of pancuronium-induced blockade that has been reported in the presence of very high serum concentrations of theophylline (38). 

Azathioprine reduces sensitivity to pancuronium in experimental animals, possibly as a result of phosphodiesterase inhibition, increasing transmitter release (SEDA-4, 87) (40), (SEDA-13,104). 

Furosemide (1 mg/kg) shortened the recovery time from pancuronium blockade in neurosurgical patients with normal renal function (46). Phosphodiesterase inhibition and... 

The CNS-stimulating effects of the methylxanthines were once attributed to their phosphodiesterase-inhibiting ability. This action is probably irrelevant at therapeutic doses. Evidence indicates that the overall CNS-stimulant action is related more to the ability of these compounds to antagonize adenosine at A and A a receptors. All of the roles of these receptors are still under study. The adenosine receptor subtypes and their pharmacology have been reviewed. -Problems with (he present compounds, such as caffeine and theophylline, are lack of receptor selectivity and (he ubiquitous nature of the various receptor subtypes. 

Some other drugs that appear to owe part of their action to phosphodiesterase inhibition include a number of naturally occurring methylxanthine drugs and their derivatives (e.g. aminophylline. caffeine, theobromine, theophylline), but they also have ADENOSINE RECEPTOR ANTAGONIST properties see BRONCHODILATORS CENTRAL STIMULANTS. 

Dulloo AG, Seydoux J, Girardier L. Potentiation of the thermogenic antiobesity effects of ephedrine by dietary methylxanthines Adenosine antagonism or phosphodiesterase inhibition Metabolism 1992 41 1233-1241. 

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