Phosphodiesterase inhibition, cyclic

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. 

Because of its ability to bind CaM, tamoxifen can increase cyclic AMP surges by inhibiting cyclic AMP hydrolysis by the Ca2+-calmodulin-dependent cyclic nucleotide phosphodiesterase (Fanidi et al. 1989 Rowlands et al. 1990). In bovine brain preparations, tamoxifen appears to act as a competitive inhibitor of calmodulin-activated phosphodiesterase with an IC50 of 2 p,M, similar to the value reported for trifluoperazine under the same experimental conditions (Lam 1984). 

A further characteristic of this principle is that, if the activity of phosphodiesterase is decreased, the concentration of cyclic GMP will increase to an extent dependent upon the extent of the decrease in activity. This characteristic has been made use of by the pharmaceutical industry. Cyclic GMP has a vasodilatory effect and this is the case for the arterioles that supply blood to the corpus cavemosum in the penis, which controls the erection of the penis. Drugs were developed (e.g. sildenafil) that inhibits cyclic GMP phosphodiesterase and hence increases the cyclic GMP level which resnlts in vasodilation of the arterioles and an increase in the snpply of blood to the spongy tissue of the corpus cavemosum, which expands resulting in erection. This dmg has been found to be effective in some patients snffering from erectile dysfunction. This can be a particular problem in diabetic patients and more elderly men (Chapter 19). 

Dipyridamole is a platelet adhesion inhibitor, although the mechanism of action has not been fully elucidated. The mechanism may relate to 1) Inhibition of red blood cell uptake of adenosine, itself an inhibitor of platelet reactivity, 2) phosphodiesterase inhibition leading to increased cyclic-3 , 5 -adenosine monophosphate within platelets and, 3) inhibition of thromboxane A2 formation,... 

Several mechanisms have been proposed for the actions of methylxanthines, but none has been firmly established. At high concentrations, they can be shown in vitro to inhibit several members of the phosphodiesterase (PDE) enzyme family (Figure 20-3). Because the phosphodiesterases hydrolyze cyclic nucleotides, this inhibition results in higher concentrations of intracellular cyclic AMP (cAMP) and, in some tissues, cGMP. CAMP is responsible for a myriad of cellular functions including, but not limited to, stimulation of cardiac function, relaxation of smooth muscle, and reduction in the immune and inflammatory activity of specific cells. 

This synthetic procedure was used to synthesize thiophene analogs of PDE-I and PDE-II such as 196, compounds able to inhibit cyclic adenosine-3, 5 -monophosphate phosphodiesterase (86JCS(CC)826). In this case, the photochemical reaction by using Pd on carbon methodology gave the product in 64% yield. 

Resveratrol ameliorates aging-related metabolic phenotypes by inhibiting cyclic adenosine monophos-phate (cAMP) phosphodiesterases (12CE421)... 

The modes of action of different alkaloids are diverse. For example, nicotine binds to and affects nicotinic acetylcholine receptors and shows toxicity. A recent molecular 3D model suggests that both acetylcholine and nicotine bind to the same pocket formed in a nicotinic acetylcholine receptor.15 Morphine binds to and activates opioid receptors, transmembrane-spanning G protein-coupled receptors, in the central nervous system of humans.16 Caffeine, which is structurally similar to adenine, inhibits cyclic AMP phosphodiesterase activity and inhibits the degradation of cAMP, thus exerting a toxic effect on insects 17 in human beings, binding of caffeine to the adenosine A2A receptor induces wakefulness.18 Atropine binds to muscarinic acetylcholine receptors, competing with acetylcholine, and blocks neurotransmission.1... 

Isolation and regulation of the cGMP-inhibited cyclic-AMP phosphodiesterase from human erythroleukemia frlEL) cells)... 

AminophyUme facilitates neuromuscular transmission, perhaps by increasing neurotransmitter release, through raising cyclic AMP concentrations at the neuromuscular junction via phosphodiesterase inhibition (37). This would account for the antagonism of pancuronium-induced blockade that has been reported in the presence of very high serum concentrations of theophylline (38). 

C.J. Smith, V. Vasta, E. Degerman, P. Belfrage, and V. Manganiello, Hormone-sensitive cyclic GMP-inhibited cyclic AMP phosphodiesterase in rat adipocytes. Regulation of insulin- and cAMP-dependent activation by phosphorylation, J. Biol. Chem., 1991, 266, 13385-13390. 

The stimulation of the octopaminergic nervous system of invertebrates is a proven strategy for the control of important pest species. This has been achieved in the past by the use of octopamine receptor agonists such as formamidine and imidazoline derivatives. However, other potential strategies to achieve this end include the inhibition of cyclic nucleotide phosphodiesterase, inhibition of the neural reuptake of octopamine, and inhibition of octopamine N-acetyltransferase. Using the American cockroach nervous system, formamidines were found to inhibit both the uptake and acetylation of octopamine, but not with a potency comparable to their effect on octopamine receptors. The tricyclic antidepressant, desipramine, and the benzylamine, xylamine, were the most active inhibitors of these octopamine removal systems. The pharmacological profiles for uptake and N-acetylation appear to be quite similar, but differ from that of the adenylate cyclase-linked octopamine receptor. 

Cyclic adenosine monophosphate (c-AMP) is a secondary messenger within cells. The c-AMP phosphodiesterase inhibition test is a useful means for screening biologically active compounds [65], Correlations of structure with inhibitory activity for lignans and their glucosides are shown in Tables 17.2-1 through 17.2-5. For... 

Dyphylline is a xanthine derivative related to theophylline. It relaxes bronchial smooth muscle and stimulates central respiratory drive. It is indicated in the relief of acute bronchial asthma and reversible bronchospasm associated with chronic bronchitis and emphysema. A large number of derivatives of the methylxanthines have been prepared and examined for their ability to inhibit cyclic nucleotide phosphodiesterases (PDFs) and antagonize receptor-mediated actions of adenosine, the two best characterized cellular actions of the methylxanthines. Although certain modifications dissociate these two activities to some degree, these compounds are not used therapeutically. 

In hypertensive subjects, 60 mg of flordipine lowered blood pressure without any accompanying changes in cardiac rate. In addition to calcium entry blockade, flordipine has been found to inhibit cyclic nucleotide phosphodiesterase. > ... 

Nucleoside antibiotic. Prod, by Strepto-myces griseoaurantiacus. Inhibits cyclic-AMP phosphodiesterase. Powder. 

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