CAMP-phosphodiesterase

Dipyridamole exerts its effect by inhibition of platelet phosphodiesterase E5, increasing cyclic guanosine monophosphate and cyclic adenosine monophosphate (cAMP). By inhibiting its uptake and metabolism by erythrocytes, dipyridamole also increases the availability of adenosine within blood vessels, promoting inhibition of platelet aggregation and local vasodilatation. " Dipyridamole may also inhibit cAMP phosphodiesterase in platelets, which further increases cAMP levels and may enhance endothelial nitric oxide production, contributing to its antithrombotic effect. Existing trials of dipyridamole in stroke have focused on secondary prevention and will be discussed briefly. 

When glucagon levels fall, cAMP phosphodiesterase destroys the accumulated cAMP, and specific protein phosphatases remove the phosphate from the phosphoproteins. These phosphatases themselves are often regulated by phosphorylation—yes, there are phosphatase kinases and phosphatase phosphatases. It s really easy to lose it here, but the key factor is that increased glucagon levels lead to increased protein phosphorylation, and decreased glucagon levels lead to decreased protein phosphorylation. 

Swinne, J., Tsikalas, K. E. and Contim, M. Properties and hormonal regulation of two structurally related cAMP phosphodiesterases from the rat Sertoli cell. /. Biol. Chem. 266 18370-18377,1991. 

Lam HY (1984) Tamoxifen is a calmodulin antagonist in the activation of cAMP phosphodiesterase. Biochem Biophys Res Commun 118 27-32... 

Martin prepared 5-trimethylstannylindole and effected coupling with bromobenzene to give 5-phenylindole [125], In a search for new cAMP phosphodiesterase inhibitors, Pearce prepared the furylindole 190 from 5-bromoindole and 5-ferr-butoxy-2-trimethylstannylfuran [196a], Benhida and co-workers explored Stille couplings of 6-bromo- and 6-iodoindole, and methyl 6-iodoindol-2-ylacetate with a variety of heteroarylstannanes and vinylstannanes [196b]. 

In adipose tissue, insulin stimulation suppresses triglyceride hydrolysis (to free fatty acids and glycerol) by activating cAMP phosphodiesterase (cAMP PDE). Cyclic AMP, (3, 5 cAMP), is required to stimulate hormone sensitive lipase (HSL), the enzyme which hydrolyses triglyceride within adipocytes PDE converts active 3, 5 cAMP to inactive 5 AMP thus preventing the stimulation of HSL. The net effect of insulin on lipid metabolism is to promote storage. 

Horowski, R. and SastreHernandez, Y.M., Clinical effects of the neurotropic selective cAMP phosphodiesterase inhibitor rolipram in depressed patients global evaluation of the preliminary reports, Curr. Ther. Res. Clin. Exp., 38, 23, 1985. 

Intracellular messengers A biphasic effect of ginkgo extract is seen on cAMP phosphodiesterase under in vitro and ex vivo conditions (Saponara and Bosisio 1998 Macovschi et al. 1987). Whereas low concentrations (0.25-4.0 mg/L) activate the enzyme, higher concentrations (5-250 mg/L), dose-dependently inhibit it. However, tolerance develops to this effect because it is undetectable after daily administration for 4 days. Thus, ginkgo may initially produce effects by inhibiting enzymatic breakdown of cAMP. This mechanism is similar to the stimulant caffeine, but it is not likely to explain any long-term effects of ginkgo because it disappears after chronic daily treatment. The responsible constituent for this effect has not been identified. 

Saponara R, Bosisio E. (1998). Inhibition of cAMP-phosphodiesterase by biflavones of Ginkgo biloba in rat adipose tissue. J Nat Prod. 61(11) 1386-87. 

The inotropic effects of these agents are not mediated via direct stimulation of -adrenergic receptors or indirectly by release of catecholamines, but by selective inhibition of cardiac cAMP phosphodiesterase (PDE) type III [25,35-40]. Recently, it has been demonstrated that the imidazole core is primarily responsible for PDE isozyme specificity, whereas the dihydropyri-dazinone moiety is responsible for inhibitory potency the phenylene moiety obviously acts mainly as a spacer [26]. A five-point model for positive inotropic activity of PDE III inhibitors has been elaborated [41]. 

Another pyridazinone-derived inotropic agent with cAMP phosphodiesterase inhibitory activity is pimobendan [UD-CG-115-BS CAS 74150-27-9, (21)], which has been developed in Germany. In contrast to the imidazolyl-phenylpyridazinone CI-930 (16) discussed above, in pimobendan the imidazole nucleus (substituted at C-2 by a 4-methoxyphenyl group) is fused to the benzene moiety attached to C-6 of the 4,5-dihydro-5-methyl-3(2//)-pyri-dazinone system. 

Activation of cAMP phosphodiesterase, which decreases levels of cAMP and thus the activity of protein kinase A. This results in decreased rates of lipolysis in adipose tissue and glycogenolysis and gluconeogenesis in liver. 

In contrast to glucagon, the peptide hormone insulin (see p. 76) increases glycogen synthesis and inhibits glycogen breakdown. Via several intermediates, it inhibits protein kinase GSK-3 (bottom right for details, see p. 388) and thereby prevents inactivation of glycogen synthase. In addition, insulin reduces the cAMP level by activating cAMP phosphodiesterase (PDE). 

Mata R, Gamboa A, Macias M, Santillan S, UUoa M, Gonzalez MC, Effect of selected phytotoxic agents from Guanomyces polythrix on the calmodulin-dependent activity of the enzymes cAMP phosphodiesterase and NAD-kinase, JAgricFood Chem 51 4559 562, 2003. 

Upon binding calcium ions, the small acidic protein known as calmodulin can activate enzymes by binding to a wide variety of proteins containing cahnodulin-binding domains. Such proteins include cAMP phosphodiesterase, calmodulin-dependent nitric oxide synthase, calmodulin kinases, the plasma membrane calcium pump, calcineurin, and calmodulin-dependent inositol-(l,4,5)-trisphosphate 3-kinase. See also Activation Autoinhibition... 

Cilostazol is a selective cAMP phosphodiesterase inhibitor. It inhibits platelet aggregation and is a direct arterial vasodilator. It is used for the symptoms of intermittent claudication in individuals with peripheral vascular disease. Side-effects of cilostazol include headache, diarrhea, increased heart rate, and palpitations. Drugs similar to cilostazol have increased the risk of death in patients with congestive heart failure. 

Griebel G, Misslin R, Vogel E, Bourguignon J (1991) Behavioral effects of rolipram and structurally related compounds in mice behavioral sedation of cAMP phosphodiesterase inhibitors. J Neurochem 58 321-323... 

A) Inhibition of cAMP phosphodiesterase in monocytic lineage leukocytes... 

D. Etanercept is a recombinant fusion protein consisting of two TNF receptor domains linked to one IgG Fc molecule. It binds to soluble TNF-a and TNF-(3 and forms inactive complexes. It does not directly affect cAMP phosphodiesterase, leukotriene synthesis, or autoantibody production. 

Mechanism of Action A positive inotropic agent that inhibits myocardial cyclic adenosine monophosphate (cAMP) phosphodiesterase activity and directly stimulates... 

Fleischhacker, W.W., Hinterhuber, H., Bauer, H., Pflug, B., Berner, P., Simhandl, C., Wolf, R., Gerlach, W., Jaklitsch, H., Sastre-y-Hernandez, M., Schmedlng-Wlegel, H., Sperner-Unterweger, B., Voet, B., and Schubert, H. (1992) A multicenter double-blind study of three different doses of the new cAMP-phosphodiesterase inhibitor rolipram in patients with major depressive disorder. Neuropsychobiology 26 59-64. 

A. R. Saltiel, J. A. Fox, P. SherUne, P. Cuatrecasas (1986). Insulin-stimulated hydrolysis of a novel glycoUpid generates modulators of cAMP phosphodiesterase. Science 233 967-972. P. R. Shepherd, B. B. Kahn (1999). Glucose transporters and insulin action—implications for insulin resistance and diabetes melUtns. N. Eng. J. Med. 341 248. 

Many bixxer compounds contain both hydrophobic and hydrophilic sites which can alter cell membranes through penetration. There is a correlation between bitter intensity and hydrophobicity-solubility indexes such as fee octanol/water partition coefficient, lo (7). Penetration may directly affect cAMP phosphodiesterase as part of fee transduction process (see below). A bitter receptor protein may be involved wife certain bitters, such as specific structural requirements wife fee bitter tasting dipeptides and denatonium salts (27). The latter is used in some consumer products to avoid accidental ingestion. A receptor mechanism is also supported by fee existence of a genetic "taste blindness" for some bitter materials (see below). 

Concentration of cAMP is controlled primarily by two means, namely via new synthesis by adenylyl cyclase and degradation by phosphodiesterases (review Houslay Milligan, 1997). In addition to adenylyl cyclase, the activity of which is subject to diverse regulation (see 5.6.1), the cAMP phosphodiesterases are also an important point of attack for control of the cAMP level. There are phosphodiesterases regulated by Ca Vcahnoduhn and by protein phosphorylation. More than 10 different isoforms of phosphodiesterase are known, which vary in their cyclic nucleotide specificity and in their regulation. 

Substituted pyrazolo[l,5-a]pyrimidines are selective inhibitors of adenosine 3, 5 -Cyclic monophosphate (CAMP) phosphodiesterases in vitro (74JMC645 75JMC460). 

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