Cyclic AMP-phosphodiesterase

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. 

Enzyme Assay. Na , K -ATPase, and sarcoplasmic reticulum Ca - ATPase were prepared from rat hearts (22) and dog hearts (23), respectively. Bovine heart cyclic AMP phosphodiesterase was purchased from Sigma. The enzyme reaction was carried out after 5-min pretreatment with the drug, and the amount of inorganic phosphate liberated during the reaction period was determined. 

Effects on Ena e Activities. MTX at concentrations up to 10" g/mL had no effect on the enzymes related to the possible mechanism of cardioexcitatory action, such as cardiac Na ,K - ATPase, cyclic AMP phosphodiesterase, and sarcoplasmic reticulum Ca -ATPase. 

MTX caused a contraction of vascular smooth muscle and positive inotropic, positive chronotropic and arrhythmogenic effects on cardiac muscle. The effect of MTX was little affected by various receptor blockers, a Na channel blocker or a catecholamine depleting agent. Further, MTX had no effect on the enzymes which were related to Ca movements, such as Na , K -ATPase, cyclic AMP phosphodiesterase, and sarcoplasmic reticulum Ca -ATPase. These results would eliminate the possible involvement of an indirect action elicited by the release of chemical mediators and direct modifications of their receptors, Na channels, or various enzymes as a major mechanism of action of MTX. 

M Gilmour Buck, JA Zadunaisky. (1975). Stimulation of ion transport by ascorbic acid through inhibition of 3, 5 -cyclic AMP phosphodiesterase in the corneal epithehum and other tissue. Biochim Biophys Acta 376 82-88. 

Iyo, M., Bi, Y., Hashimoto, K., Inada, T., Fukui, S. Prevention of methamphetamine-induced behavioral sensitization in rats by a cyclic AMP phosphodiesterase inhibitor, rolipram. Eur. J. Pharmacol. 312 163, 1996. 

McPhee, I., Pooley, L., Lobban, M., Bolger, G. and Houslay, M. D. Identification, charactirization and regional distribution in brain of RPDE-6 (RNPDE4A5), a novel splice variant of the PDE4A cyclic AMP phosphodiesterase family. Biochem. J. 310 965-974,1995. 

Rowlands MG, Parr IB, McCague R, Jarman M, Goddard PM (1990) Variation of the inhibition of calmodulin dependent cyclic AMP phosphodiesterase amongst analogues of tamoxifen correlations with cytotoxicity. Biochem Pharmacol 40 283-289... 

Macovschi 0, Prigent AF, Nemoz G, Pacheco FI. (1987). Effects of an extract of Ginkgo biloba on the 3, 5 -cyclic AMP phosphodiesterase activity of the brain of normal and triethyltin-intoxicated rats. J Neurochem. 49(1) 107-14. 

Glucagon stimulates adenylate cyclase activity and this increases the concentration of cyclic AMP. Insulin antagonises this effect via an increase in the activity of cyclic AMP phosphodiesterase, which hydrolyses cyclic AMP to AMP, which results in a decrease in the concentration of cyclic AMP (Figure 6.34). 

A naturally occurring substance (1,3,7-trimethytxan-thine) that competitively inhibits 3, 5 -cyclic AMP phosphodiesterase and acts as a powerful central nervous system stimulant. The inhibitory effect can be reversed at high cAMP concentrations. A related substance, theophylline (also known as aminophylhne) has a similar mode of action. 

Several methyixanthines produced by plants are inhibitors of cyclic AMP phosphodiesterase and thereby produce an elevation in cyclic AMP levels in cells throughout the body. 

C. Aspirin inhibits platelet cyclooxygenase. Abciximab, a monoclonal antibody, binds to and inhibits the platelet glycoprotein Ilb/IIIa receptor. Dipyridamole inhibits platelet cyclic AMP phosphodiesterase and raises cyclic AMP levels. Eptifibatide binds to the glycoprotein Ilb/IIIa complex. 

Sankawa. Inhibition of cyclic AMP phosphodiesterase by lignans and cou-marins of Olea and Fraxinus barks. Shoyakugaku Zasshi 1986 40(1) ... 

It is relatively selective inhibitor of peak III cyclic AMP phosphodiesterase isoenzyme in cardiac and vascular muscle. In patients with CHF, it produces dose related and plasma concentration related increase in the maximum rate of increase of left ventricular pressure. Milrinone has a direct inotropic and direct arterial vasodilator activity. It is administrated by IV infusion 0.50 mg/kg over 10 min with a maximum daily dose of 1.13 mg/kg. 

With the aim of developing new analogues of the cyclic AMP phosphodiesterase inhibitor lixazinone (554), the synthesis of agents 553 and 555-557 was undertaken (Scheme 167) (88JMC2136). Thus, all possible 1,2-related N-r-Boc aldehydes 551 were prepared by directed metalation on isomers 549, with the exception of that which required the use of a metal-halogen exchange reaction on the bromo precursor 550 (attempts to metalate 4-TMS-3-N-f-Boc pyridine proved inefficient). As exemplified for one particular isomer, conversion of 551 into 552 by reductive amination... 

Ethyl l-oxo-6-piperidino-l//-pyrimido[l,2-a]quinoline-2-carboxylate showed potent in vitro anticoccidial activity (92AAC2338). anhydro-1,3-Diethyl-2-hydroxy-4-oxo-4//-pyrimido[2,l-a]isoquinolinium hydroxyde (318) exhibits nonselective Ar and A2-adenosine receptor activities (84JMC1364) and proved to be an inhibitor of cyclic-AMP phosphodiesterase (81JMC1284). 8,9,10,ll-Tetrahydro-3-(l//-5-tetrazolyl)-4//-pyrimido[2,l-a]iso-quinolin-4-one exhibits antiulcer activity (84USP4457932). 

When the systemic need has been satisfied there should be a way of reversing the hormone triggered process. All of the effects we have seen are promptly reversed when the need for them has ended. Cyclic AMP is hydrolyzed to 5 -AMP by an enzyme called cyclic AMP phosphodiesterase, and protein phosphatases catalyze the hydrolytic re-... 

Compound 2 is a potent cyclic AMP phosphodiesterase inhibitor, and can be prepared in almost quantitative yield by treatment of 1 with 1.1 equivalents of sodium methoxide in refluxing methanol for 15-30 minutes. When either 1 or 2 is refluxed with excess of sodium methoxide in methanol, however, the quinoline derivative 3 is obtained in 92% yield. 

Miss Muxdroozol seems to be unaffected. Perhaps her body rapidly metabolizes the compounds to methyluric acids, or what is more probable is that she has no cyclic AMP phosphodiesterases with which the stimulants normally react. 

Cinnamic acid hydroxylase Cyclic AMP phosphodiesterase Diamine oxidase... 

Giannattasio, M., Sica, G., and Macchia, V., Cyclic AMP phosphodiesterase from dormant tubers of Jerusalem artichoke, Phytochemistry, 13, 2729-2733, 1974. 

The betaine derivatives (527), 6,7-dihydro-5,7-dioxo-5//-thiazolo[3,2-a]pyrimidinium hydroxides, have been tested as inhibitors of cyclic AMP phosphodiesterase and found to have theophylline-like activity (78JPS1762). 

The heteroaromatic betaines, [l,3,4]thiadiazolo[3,2-a]pyrimidine-5,7-diones (753), which are isoconjugate with methylated xanthines, are in the same way as the latter found to be inhibitors of cyclic AMP phosphodiesterase (78JPS1762). The N-/3-D-ribofuranosyl nucleoside (754) inhibits the synthesis of RNA and DNA but not of protein. The primary blockade is in the synthesis of purine nucleotides (79MI42902). RNA synthesis is also inhibited by [l,3,4]thiadiazolo[3,2-a]pyrimidines of structure (755). The activity is attributed to the chemical reactivity at C-2 leading to reactions with an SH or OH group in RNA polymerase (80ABC1923). Compounds with the 7-oxo formula (756) are claimed to be useful as immune enhancers (78GEP2712932). 

Calcium, via calmodulin, also activates cyclic AMP phosphodiesterases which inactivate cyclic AMP by metabolism to AMP. Inhibition of phosphodiesterase yields a small increase in ACTH-stimulated steroidogenesis [2], This is relatively slight in the adrenocortical zona fasciculata-reticularis cell, which has a low phosphodiesterase level the zona glomerulosa cell has a higher activity [60,61], which may result from higher level of activation of the calcium/calmodulin intracellular messenger system in the zona glomerulosa. 

Other evidence for the involvement of a G-protein in the action of insulin has come from studies by Walaas and co-workers [104]. They have demonstrated that insulin stimulated the activity of a cyclic AMP-dependent protein kinase activity in sarcolemma membranes. As this effect of insulin was enhanced if micromolar concentrations of GTP-binding protein were present, they suggested that a guanine nucleotide regulatory protein was involved in the hormonal control of this kinase. Indeed, cholera toxin also appeared to obliterate this action of insulin, as it did the effect of insulin on liver adenylate cyclase and the peripheral plasma membrane cyclic AMP phosphodiesterase in liver. 

---