Phosphodiesterases

Phosphodiesters include nucleic acids, phospholipids, and others. These compounds are labile and actively involved in biological cycling of phosphorus and are known to be important sources of DIP in aquatic environment (Chrost and Siuda, 2002). Turnover time of these compounds is short because of their rapid enzymatic hydrolysis by phosphodiesterases. The absolute quantity of DIP release during the hydrolysis of these compounds has not been determined in wetland soils. In aquatic environment, phosphodiesters were found to be one of the major sources of DIP in the water column. For example, enzymatically hydrolysable extracellular DNA contributes approximately 

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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),... 

In addition, vinpocetine selectively inhibits a specific calcium, calmodulin-dependent cycHc nucleotide phosphodiesterase (PDF) isozyme (16). As a result of this inhibition, cycHc guanosine 5 -monophosphate (GMP) levels increase. Relaxation of smooth muscle seems to be dependent on the activation of cychc GMP-dependent protein kinase (17), thus this property may account for the vasodilator activity of vinpocetine. A review of the pharmacology of vinpocetine is available (18). 

Initially, it was beheved that the abiUty of xanthines phosphodiesterase (PDF) led to bronchodilation (Fig. 2). One significant flaw in this proposal is that the concentration of theophylline needed to significantly inhibit PDE in vitro is higher than the therapeutically useful semm values (72). It is possible that concentration of theophylline in airways smooth muscle occurs, but there is no support for this idea from tissue distribution studies. Furthermore, other potent PDE inhibitors such as dipyridamole [58-32-2] are not bronchodilators (73). EinaHy, although clinical studies have shown that neither po nor continuous iv theophylline has a direct effect on circulating cycHc AMP levels (74,75), one study has shown that iv theophylline significant potentiates the increase in cycHc AMP levels induced by isoproterenol (74). 

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. 

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... 

FIGURE 11.31 Snake venom phosphodiesterase and spleen phosphodiesterase are exonncleases that degrade polynncleotides from opposite ends. 

Snake venom phosphodiesterase Both a Starts at 3 -end, 5 -NMP products... 

The cAMP formed by adenylyl cyclase (Figure 15.20) does not persist because 5 -phosphodiesterase activity prevalent in cells hydrolyzes cAMP to give 5 -AMP. Caffeine inhibits 5 -phosphodi-esterase activity. Describe the effects on glycogen phosphorylase activity that arise as a consequence of drinking lots of caffeinated coffee. 

Sircar and co-workers reported that some pyrazol-3-ones possess potent and selective inhibitory phosphodiesterase activity which is primarily responsible for their inotropic action (87JOC1724). 

FIGURE 2.6 Production of cyclic AMP from ATP by the enzyme adenylate cyclase. Cyclic AMP is a ubiquitous second messenger in cells activating numerous cellular pathways. The adenylate cyclase is activated by the a subunit of Gs-protein and inhibited by the a-subunit of Gj-protein. Cyclic AMP is degraded by phosphodiesterases in the cell. 

FIGURE 2.19 Potentiation and modulation of response through control of cellular processes, (a) Potentiation of inotropic response to isoproterenol in guinea pig papillary muscle by the phosphodiesterase inhibitor isobutylmethylxanthine (IBMX). Ordinates percent of maximal response to isoproterenol. Abscissa percent receptor occupancy by isoproterenol (log scale). Responses shown in absence (open circles) and presence (filled circles) of IBMX. Data redrawn from [7], (b) Effect of reduction in calcium ion concentration on carbachol contraction of guinea pig ileum. Responses in the presence of 2.5 mM (filled circles) and l.5mM (open circles) calcium ion in physiological media bathing the tissue. Data redrawn from [8],... 

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. 

Imidazo[l,2-c/][l,2,4]triazines 488 were prepared (78USP4096257) from the reaction of 2-imidazocarboxylic acid hydrazide 487 with orthoesters. They inhibited cyclic-AMP phosphodiesterase in the mouse skin phosphodiesterase test and had antiasthina. 

The tethering of PKA through AKAPs by itself is not sufficient to compartmentalize and control a cAMP/ PKA-dependent pathway. Cyclic AMP readily diffuses throughout the cell. Therefore, discrete cAMP/PKA signalling compartments are only conceivable if this diffusion is limited. Phosphodiesterases (PDE) establish gradients of cAMP by local hydrolysis of the... 

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