Inhibition of cAMP phosphodiesterase

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. 

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

Carboline-l-propionic acid Inhibition of cAMP phosphodiesterase 357... 

Semmler, J., Gebert, U., Eisenhut, T. et al. Xanthine derivatives comparison between suppression of tumor necrosis factor-a production and inhibition of cAMP phosphodiesterase activity. Immunology 1993, 78, 520-525. 

It shows considerable inhibition of cAMP-phosphodiesterase in rat adipose tissues and inhibits non-enzymic lipid peroxidation. It is a potent scavenger of superoxide and increases the beat rate on isolated atria, stimulates lipolysis and causes a concentration-dependent increase in Ca release from the heavy fraction of fragmented sarcoplasmic reticulum of rabbit skeletal muscle. ... 

Amic, D., Davidovic-Amic, D., Juric, A., Lucic, B. and Trinajstic, N. (1995a) Structure-activity correlation of flavone derivatives for inhibition of cAMP phosphodiesterase. J. Chem. Inf. Comput. Sci., 35, 1034-1038. 

TABLE I. Inhibition of cAMP Phosphodiesterase from Cockroach CNS... 

At a screening concentration of 1.0 mM, none of these compounds gave noteworthy inhibition. The known phosphodiesterase inhibitors theophylline, isobutyl-3-methylxanthine (IBMX), and papaverine caused considerable inhibition at 1 mM and had IC50 values between 0.1 and 1.0 mM. It therefore seems unlikely that the excitatory effects caused by these octopaminergic agonists in invertebrates can be related to inhibition of cAMP phosphodiesterase activity. 

Some information is available on the chemical differences between members of a pair of analogous enzymes. Thus the enzyme that hydrolyses cyclic adenosine monophosphate (cAMP) has been shown to have different molecular composition when specimens from different mammalian tissues were compared (Weiss and Fertel, 1977). Relevantly, pyruvate kinase from healthy liver (L), kidney (K), and muscle (M) of the rat gave inhibitory ratios (L K M) of 1 7.6 6 with 3 -methoxy-ADP, of 1 1.2 7.1 with 8-ethylamino-ADP, and 3 2 1 with methyl-(AT-acetyl-ci) methylaminobutyl)-ADP (Hai, Abo and Hampton, 1982). Similarly, small changes in the substituents inserted into pyrazolo-[1,5-fl]-l, 3,5-triazine 4.53) bring about an inhibition of cAMP phosphodiesterase in different tissues from this list bovine brain, bovine heart, or rabbit lung (Senga etal., 1982). 

Modulation of second-messenger pathways is also an attractive target upon which to base novel antidepressants. Rolipram [61413-54-5] an antidepressant in the preregistration phase, enhances the effects of noradrenaline though selective inhibition of central phosphodiesterase, an enzyme which degrades cycHc adenosiae monophosphate (cAMP). Modulation of the phosphatidyl iaositol second-messenger system coupled to, for example, 5-HT,, 5-HT,3, or 5-HT2( receptors might also lead to novel antidepressants, as well as to alternatives to lithium for treatment of mania. Novel compounds such as inhibitors of A-adenosyl-methionine or central catechol-0-methyltransferase also warrant attention. 

Methylxanthines have relaxing and anti-inflammatory effects. Accumulation of intracellular cAMP by inhibition of PDE3 (phosphodiesterase-3) relaxes airway... 

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 the hormonal stimulus stops, the intracellular actions of cAMP are terminated by an elaborate series of enzymes. cAMP-stimulated phosphorylation of enzyme substrates is rapidly reversed by a diverse group of specific and nonspecific phosphatases. cAMP itself is degraded to 5 -AMP by several cyclic nucleotide phosphodiesterases (PDE Figure 2-13). Competitive inhibition of cAMP degradation is one way caffeine, theophylline, and other methylxanthines produce their effects (see Chapter 20). 

A) Inhibition of platelet phosphodiesterases (PDEs) [91]. Quercetin and myricetin potentiated the anti-aggregatory action of prostacyclin (PGI2), a potent stimulator of platelet adenylate cyclase synthesised by the vascular endothelium, on ADP-induced platelet aggregation in washed human platelets, and the elevation of platelet cyclic adenosine monophosphate (cAMP) elicited by PGI2 [89,92,93]. These effects are probably due to an inhibition of PDEs. As suggested by Ferrell and co-workers [92], this inhibition arises from the similarity between the pyranone ring of flavonoids and the pyrimidine ring of adenine. 

Forskolin stimulates die catalytic subunit of adenylyl cyclase directly, bypassing the G proteins, which makes forskolin a much used substance in experiments with elevated platelet cAMP-levels. A number of agents has been demonstrated to inhibit the cAMP phosphodiesterases in platelets, e.g. papaverine, dipyridamole and the methylxantines... 

An experimental study into the mechanism of action of enoximone in 14 patients with ischaemic or idiopathic dilative cardiomyopathy found that pretreatment with intravenous aminophylline 7 mg/kg given over 15 minutes reduced the beneficial haemodynamic eflects of intravenous enoximone 1 mg/kg given over 15 minutes. This appears to occur because each drug competes for inhibition of cAMP specific phosphodiesterases in cardiac and vascular smooth muscle. Milrinone, another phosphodiesterase inhibitor similar to enoximone, would be expected to interact in the same way. However, there are, at present, no published reports of a possible interaction with milrinone, and no case reports of a problem occurring with the concurrent use of either drug with theophylline. The clinical importance of this study therefore awaits evaluation. 

Little is known about the regulation of cAMP phosphodiesterase activity except that most mammalian enzymes are activated by imidazoles and inhibited by methyl xanthines. An effect of insulin on the diesterase has been claimed but not confirmed, and insulin is generally believed to interfere with lipolysis by inhibiting the cyclase. 

Dipyridamole (Fig. 19.7) is an inhibitor of phosphodiesterase, which is responsible for the breakdown of cydic AMP. Inhibition of cAMP breakdown in some way inhibits the effect of ADP binding to platelets. In addition, dipyridamole inhibits the breakdown of adenosine to adenine thus the dmg raises extracellular levels of adenosine. Adenosine is an inhibitor of platelet a r ation. 

Phosphodiesterase Inhibitors. Because of the complexity of the biochemical processes involved in cardiac muscle contraction, investigators have looked at these pathways for other means of dmg intervention for CHF. One of the areas of investigation involves increased cycHc adenosine monophosphate [60-92-4] (cAMP) through inhibition of phosphodiesterase [9025-82-5] (PDE). This class of compounds includes amrinone, considered beneficial for CHF because of positive inotropic and vasodilator activity. The mechanism of inotropic action involves the inhibition of PDE, which in turn inhibits the intracellular hydrolysis of cAMP (130). In cascade fashion, cAMP-catalyzed phosphorylation of sarcolemmal calcium-channels follows, activating the calcium pump (131). A series of synthetic moieties including the bipyridines, amrinone and milrinone, piroximone and enoximone, [77671-31-9], C22H22N2O2S, all of which have been shown to improve cardiac contractiUty in short-term studies, were developed (132,133). These dmgs... 

Increased lipid synthesis/inhibi-tion of lipolysis Activation of lipoprotein lipase (LPL)/induc-tion of fatty acid synthase (FAS)/inactivation of hormone sensitive lipase (HSL) Facilitated uptake of fatty acids by LPL-dependent hydrolysis of triacylglycerol from circulating lipoproteins. Increased lipid synthesis through Akt-mediated FAS-expression. Inhibition of lipolysis by preventing cAMP-dependent activation of HSL (insulin-dependent activation of phosphodiesterases )... 

Figure 25-8. Control of adipose tissue lipolysis. (TSH, thyroid-stimulating hormone FFA, free fatty acids.) Note the cascade sequence of reactions affording amplification at each step. The lipolytic stimulus is "switched off" by removal of the stimulating hormone the action of lipase phosphatase the inhibition of the lipase and adenylyl cyclase by high concentrations of FFA the inhibition of adenylyl cyclase by adenosine and the removal of cAMP by the action of phosphodiesterase. ACTFI,TSFI, and glucagon may not activate adenylyl cyclase in vivo, since the concentration of each hormone required in vitro is much higher than is found in the circulation. Positive ( ) and negative ( ) regulatory effects are represented by broken lines and substrate flow by solid lines.

Milrinone and inamrinone work by inhibiting phosphodiesterase III, the enzyme responsible for the breakdown of cAMP. The increase in cAMP levels leads to increased intracellular calcium concentrations and enhanced contractile force generation. Milrinone has replaced inamrinone as the phosphodiesterase inhibitor of choice due to the higher frequency of thrombocytopenia seen with inamrinone. 

Three major mechanisms of action have dominated as possible explanations for the ergogenic potential of caffeine in the enhancement of exercise performance. These three mechanisms involve (1) the mobilization of intracellular calcium from the sarcoplasmic reticulum of skeletal muscle, (2) the increase of cyclic-3 ,5 -adenosine monophosphate (cAMP) by the inhibition of phosphodiesterases in muscles and adipocytes, and (3) the competitive antagonism of adenosine receptors, primarily in the central nervous system (CNS).8 9... 

A short-acting platelet inhibitor called dipyridamole functions by maintaining a high level of cAMP within the platelets by inhibiting the enzyme phosphodiesterase, which would otherwise degrade cAMP. It also raises the adenosine concentration in plasma by decreasing its cellular uptake and degradation (70). 

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