Enzyme inhibitors phosphodiesterase

The biosynthesis of the IL-12 cytokine is dependent upon various enzymes, including phosphodiesterase 4 (PDE4). Thus, PDE4 enzyme inhibitors act as functional IL-12 antagonists, and may have clinical application in the treatment of rheumatoid arthritis. 

Viagra is a phosphodiesterase-5 enzyme inhibitor. It was not made to treat impotence—that was a side effect—almost not discovered because men in Phase II did not want to talk about unwanted erections. 

Answer In the case of enzyme antagonists, a basal stimulation of the system may be required to observe any effect of enzyme inhibition. In this case, the enzyme is phosphodiesterase (PDE), which hydrolyzes elevated levels of cytosolic cyclic AMP. In vivo, the heart is under a tonic sympathetic (3-adrenoceptor stimulation, but the cardiotonic effect of this stimulation is kept to a subthreshold level by the hydrolysis of the resulting cyclic AMP by PDE. Inhibition of this braking effect through inhibition of PDE allows the cyclic AMP levels in the cell to be elevated with a resulting positive inotropic effect. Without this stimulation of the system, no effect of PDE blockade will be observed. In terms of system stimulation, a PDE inhibitor will potentiate the effects of a (3-adrenoceptor agonist. If the in vitro assay is placed under a subthreshold level of (3-adrenoceptor stimulation, then blockade of PDE will potentiate the subthreshold effect to a visible effect, that is, a curve will appear with PDE blockade (see Figure 14.25). Therefore, the in vitro cardiac preparation should be carried out with a subthreshold level of (3-adrenoceptor stimulation to better simulate in vivo conditions. 

Other useful enzyme inhibitors include acetazolamide (Diamox) (carboific anhydrase inhibitor) for the treatment of glaucoma, congestive heart failure, epilepsy and motion sickness (a very useful drug ). Sildenafil (Viagra), famous for treatment of impotence, inhibits a phosphodiesterase enzyme (PDE5) that is involved in the breakdown of ATP. 

Caffeine is a potent inhibitor of the enzyme cAMP phosphodiesterase. Which of the following conseqnences would you expect to occur in the liver after drinking two cups of strong expresso coffee ... 

PDE inhibitor Phosphodiesterase inhibitor a drug that inhibits one or more enzymes that degrade cAMP (and other cyclic nucleotides). Examples amrinone, high concentrations of theophylline... 

Caffeine is one of a group of substances called methylxanthines. They are closely similar compounds to adenine and guanine, which are building blocks in the nucleotides AMP, ADP, ATP and GMP, GDP and GTP. Caffeine is the main stimulant substance in coffee but similar compounds, theophylline and theobromine, are found in cocoa and tea. All of them promote wakefulness. Caffeine is the stimulant in such drinks as Red Bull. One of the sites of action of these substances is the enzyme cAMP phosphodiesterase, where they act as inhibitors (see Appendix 13). This effectively keeps the systems that are activated by cAMP switched on. It is now known also that these compounds have another site of action in the brain and elsewhere. In these locations there are inhibitory adenosine receptors, upon which caffeine acts as an antagonist. 

In recent years, not a few scientific articles have been published about the eoun-terfeiting of heibal preparations and dietary supplements intended for the treatment of male sexual dysfunction (erectile dysfunction). The earliest reports appeared around the turn of the millennium, soon after the introduction of the first phosphodiesterase enzyme inhibitor drag called sildenafil (Viagra ) in 1998 (Fig. 3.51). Subsequently, an increasing number of articles detected the illegal use of sildenafil or its analogues in preparations of heibal origin . 

Viagra is a trade name marketed by Pfizer Pharmaceutical Company and is chemically sidenafil citrate. Researchers did not start CTeating a drug for impotence. The chemical compound was developed originally for angina (severe but tanporary attack of cardiac pain) and is chemically an inhibitor for an enzyme phosphodiesterase (see the previous section, for example, for the idea of enzyme inhibitor). The drug was not successful in treating heart problems, but many of the test subjects reported their successes in bedroom activity. It turned out that the compound inhibits... 

Inhibitors of cAMP phosphodiesterase Inhibitors of fungal enzymes Inhibitors of mitochondrial respiration Inhibitors of oxidases Enzymes... 

Beyond pharmaceutical screening activity developed on aminothiazoles derivatives, some studies at the molecular level were performed. Thus 2-aminothiazole was shown to inhibit thiamine biosynthesis (941). Nrridazole (419) affects iron metabohsm (850). The dehydrase for 5-aminolevulinic acid of mouse liver is inhibited by 2-amino-4-(iS-hydroxy-ethyl)thiazole (420) (942) (Scheme 239). l-Phenyl-3-(2-thiazolyl)thiourea (421) is a dopamine fS-hydroxylase inhibitor (943). Compound 422 inhibits the enzyme activity of 3, 5 -nucleotide phosphodiesterase (944). The oxalate salt of 423, an analog of levamisole 424 (945) (Scheme 240),... 

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. 

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. 

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). 

One of the primary mechanisms for regulation of phosphodiesterase enzyme activity is phosphorylation 374 Phosphodiesterase inhibitors show promise as pharmacotherapeutic agents 374... 

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... 

Methyixanthines are inhibitors of the enzyme phosphodiesterase, preventing breakdown of and increasing intracellular levels of cAMP (Serafin 1996 Snyder and Sklar 1984). However, this action also only occurs in the millimolar range, at concentrations 100 times greater than those normally achieved (10-50 pM). 

Phosphorylation of cardiac calcium-channel proteins increases the probability of channel opening during membrane depolarization. It should be noted that cAMP is inactivated by phosphodiesterase. Inhibitors of this enzyme elevate intracellular cAMP concentration and elicit effects resembling those of epinephrine. 

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