Inhibitors of Other Phosphodiesterases

Eisai [115]. We should note, however, that no selectivity data have been published for these compounds. 

In contrast to the other members of the PDE family, PDE1 is unique in its ability to interact with calmodulin. As would be expected therefore, this interaction can also be the target of potential inhibitors. This appears to be so for some natural-product inhibitors of PDE1 isolated from ginseng root. The ginsenosides Rb, Rc, and Re are moderately active (5-15 pM) steroidal inhibitors of CaM PDE isolated 

---

Phosphodiesterase Inhibitors — LM 209 (19) has been shown to be a noncompetitive inhibitor of lung phosphodiesterase (PDE) (2.5 x 10 4M) in contrast to theophylline, which is a competitive inhibitor. 19 is antihistaminic, orally effective and inhibits bronchospasm provoked by histamine, serotonin or citric acid. It is distinguished from other antihistamines by its lack of sedation and long duration of action. Absorption, distribution and elimination studies in rat and dog after i.v. or oral administration have been reported. ... 

These kinases phosphorylate specific proteins that may be involved in removal or sequestration of Ca " " or other ions, resulting in physiological stimuli. The physiological actions of cGMP are terminated by its conversion to 5 -GMP by cGMP-phosphodiesterase. Inhibitors of cGMP phosphodiesterase promote the actions of NO. 

There are, however, other pieces of evidence that may indirectly suggest a role for a rhodopsin photoreceptor in Fabrea salina. In fact, preHminary experiments have shown that phototaxis is drastically reduced in the presence of hydroxylamine, which is known to interfere with the retinal-lysine binding in rhodopsins, and is strongly affected in the presence of zaprinast, a specific inhibitor of the phosphodiesterase known to be an essential component of the sensory transduction in vertebrate vision. In both cases, cell motflity is not affected by the presence of the drugs. 

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). 

Some other examples of metal-catalyzed substitutions are given in Scheme 11.10. Entries 1 to 3 are copper-catalyzed reactions. Entry 1 is an example of arylation of imidazole. Both dibenzylideneacetone and 1,10-phenanthroline were included as ligands and Cs2C03 was used as the base. Entry 2 is an example of amination by a primary amine. The ligand used in this case was (V,(V-diethyl sal icyl amide. These conditions proved effective for a variety of primary amines and aryl bromides with both ERG and EWG substituents. Entry 3 is an example of more classical conditions. The target structure is a phosphodiesterase inhibitor of a type used in treatment of asthma. Copper powder was used as the catalyst. 

O Donnell, J.M. (1993) Antidepressant-like effects of rolipram and other inhibitors of cyclic adenosine monophosphate phosphodiesterase on behavior maintained by differential reinforcement of low response rate. / Pharmacol Exp Tfcer 264(3) 1168-1178. 

An entire new field of therapeutics arose with the serendipitous discovery of the effect on erectile function of sildefanil (see Chapter 15), far better known as Viagra . The enormous and still rising market opened by that drug has predictably led to the search for other inhibitors of phosphodiesterase 5, the enzyme responsible for this activity. The stmctures of many follow-on agents have hewed fairly close to the original PDE 5 inhibitor. Others, such as avanafil (58-9), differ markedly from sildefanil in structure. The synthesis of this agent in effect consists of a series of displacement reactions. Thus, reaction of the benzylamine (58-1) with chloropyrimidine... 

As long as the couple are not stressed by the sexual position they use, there is no evidence of increased cardiac stress to a man or woman. Man on top, woman on top, side to side, oral sex, and masturbation are cardiologically equivalent. In homosexual relationships, other than casual, anal intercourse is not associated with increased cardiac stress provided proper lubrication is used and amyl nitrate ( poppers ) are not used in the presence of a phosphodiesterase type-5 (PDE-5) inhibitor by the patient or partner. 

Since cyclic AMP derivatives and inhibitors of cyclic nucleotide phosphodiesterase stimulate prolactin release (17, 37, 38) and dopamine is a potent inhibitor of prolactin secretion (1, ly 39), it is not surprising that the catecholamine does not stimulate the adenylate cyclase system. On the contrary, the data summarized above show that the pituitary DA receptor is negatively coupled to adenylate cyclase. The pituitary DA receptor is thus a typical DA -receptor (40, 41). In view of the multiplicity of factors involved in the control of prolactin secretion, including sex steroids, it is likely that mechanisms other than cyclic AMP are involved (39, 42). It does however appear that inhibition of cyclic AMP formation by dopamine is a key element in a multifactorial control system responsible for the fine tuning of prolactin secretion. 

CALCIUM CHANNEL BLOCKERS POTASSIUM CHANNEL ACTIVATORS t hypotensive effect Additive effect Avoid co-administration of nicorandil with phosphodiesterase type 5 inhibitors. With other drugs, monitor BP closely... 

The erectile dysfunction group of drugs, of which sildenafil is most common, are potent inhibitors of cyclic guanosine monophosphate-specific phosphodiesterase type 5 (PDE-5). The other two available drugs are tadalafil (Cialis) and... 

For other small molecules, the mechaiusm of action is still unclear. For example, sildenafil and structural analogs have recently been shown to correct trafficking of deltaF508 CFTR mutants (19, 21). Sildenafil is an inhibitor of phosphodiesterase activity however, the link between this function and CFTR trafficking correction remains to be elucidated. 

Interactions. An important footnote to the use of nitrates (and NO-dilators generally) has been the marked potentiation of their vasodilator effects observed in patients taking the phosphodiesterase (PDE) inhibitor sildenafil (Viagra). This agent targets an isoform of PDE (PDE-5) expressed in the blood vessel wall. Other methylaxanthine PDE inhibitors, such as theophylline, do not cause a similar interaction because they are rather weak inhibitors of PDE-5, even at the doses effective in asthma. A... 

Like other bacterial ADP-ribosylating toxins (e.g. diphtheria toxin. Pseudomonas aeruginosa exotoxin A, cholera toxin, pertussis toxin, and C. botulinum C2 toxin (Aktories and Just, 1993)), C3 is a mono-ADP-ribosyltransferase (Aktories et ai, 1988b). Treatment of ADP-ribosylated Rho with phosphodiesterase releases 5 -AMP and not phosphoribosyl-AIVtP, a cleavage product of poly(ADP-ribose) (Aktories et ai, 1988b Rubin ef a/., 1988). Accordingly, thymidine, an inhibitor of poly(ADP-ribose)polymerase, does not block C3-like ADP-ribosyltransferases, and can be included in C3 ADP-ribosylation assays to block poly-ADP-ribosylation reactions. 

---