Phosphodiesterase models

Calix[4]arenes as dinuclear metallo-phosphodiesterase models 00CSR75. 

P. Molenveld, J. E. J. Engbersen, D. N. Reinhoudt, Dinuclear metallo-phosphodiesterase models apphcation of calix[4]arenes as molecular scaffolds, Chem. Soc. Rev., 2000, 29, 75-86. 

The separation of the two zinc centers in the biomimetics has been shown to be important. Meyer et al. correlated the hydrolytic activity of dizinc phosphodiesterase models (Table 4.1, Fig. 4.2, Lg and Lp) with their Zn - Zn distances [38]. Here, the length of the ligand side chains determines the Zn -Zn separation. The distance of the two Zn(ll) ions in the complex with Lq is rather short with 3.4 A, while the metal ions are separated by more than 4.1 A with ligand Lp. The authors proposed that the separation of the Zn(II) centers is significant in terms of the ability of the metal complexes to efficiently catalyze the hydrolysis of the substrate, in this case BPNPP [38]. The kcat for the Zn(II) complex [Zn2(LpH i)(Me0H)(0H)](C104)2, where the Zn(II) ions have a greater... 

The first dinucleotide cleavage with the trinuclear zinc complex was reported shortly afterwards pseudo-first order rate constants were determined and a pronounced selectivity for the 3, 5 -GpG RNA homodinucleotide was discovered [87]. These new dinuclear metallo-phosphodiesterase models were reviewed in 2000, and compared with other less efficient existing models [88]. 

FIGURE 50-5 A model for the transduction of odors in OSNs. The individual steps are detailed in the text. Note that several feedback loops modulate the odor response, including inhibition of the CNG channel by Ca2+ ions (purple balls) that permeate the channel, and a Ca2+/calmodulin (CaM) -mediated desensitization of the channel that underlies rapid odor adaptation. Several other mechanisms, including phosphodiesterase-mediated hydrolysis of the second messenger, cAMP, and phosphorylation of the OR by various kinases, have also been described. 

Guanylate cyclase signaling pathway also utilizes an enzyme-linked receptor model. The effector enzyme, guanylate cyclase, converts GTP to cGMP, which in turn activates cGMP dependent protein kinase or phosphodiesterases. 

The inotropic effects of these agents are not mediated via direct stimulation of -adrenergic receptors or indirectly by release of catecholamines, but by selective inhibition of cardiac cAMP phosphodiesterase (PDE) type III [25,35-40]. Recently, it has been demonstrated that the imidazole core is primarily responsible for PDE isozyme specificity, whereas the dihydropyri-dazinone moiety is responsible for inhibitory potency the phenylene moiety obviously acts mainly as a spacer [26]. A five-point model for positive inotropic activity of PDE III inhibitors has been elaborated [41]. 

A recent report from the U. K. deals with 1,4-bis(oxodihydropyridazin-yl)benzenes and congeners which are also potent phosphodiesterase inhibitors and inodilators [159], This investigation, together with computer-aided modelling studies on various phosphodiesterase III inhibitors [160], may well stimulate the rational design of additional pyridazine-derived inodilators. 

Another drug that has been found to have anticytokine activity is pentoxifylline. It was initially characterized as a haemorheologic agent for the treatment of peripheral vascular diseases [141]. In addition, it was also found to be capable of inhibiting the pro-inflammatory actions of IL-1 and TNEa on neutrophil function and cytokine production by monocytic cells [142]. Its mechanism of action is the inhibition of phosphodiesterases, leading to increased intracellular levels of cyclic adenosine monophosphate [143]. Besides its effects on the cytokine network, pentoxifylline also exerted an anti-fibrogenic action in cultures of fibroblasts and in animal models of fibrosis [144] and could therefore be an attractive candidate for targeting hepatic inflammation. 

The determinants of calcium sensitivity, ie, the curve relating the shortening of cardiac myofibrils to the cytoplasmic calcium concentration, are incompletely understood, but several types of drugs can be shown to affect calcium sensitivity in vitro. Levosimendan is the most recent example of a drug that increases calcium sensitivity (it may also inhibit phosphodiesterase) and reduces symptoms in models of heart failure. 

Administration of a cocktail containing eicosapentenoic acid and docosahexenoic acid to volunteers for up to 6 weeks, resulted in a significant depression in IL-1J3 (61%), IL-1 a (39%), and TNF (40%) synthesis. These levels returned to normal after a few weeks [99]. In vitro studies indicate that Pentoxifylline can block the effects of IL-1 and TNF on neutrophils [100]. It is a phosphodiesterase (PDE) inhibitor that causes increased capillary blood flow by decreasing blood viscocity and is used clinically in chronic occlusive arterial disease of the limbs with intermittent claudication. Denbufylline, a closely related xanthine, has been patented as a functional inhibitor of cytokines and exhibits a similar profile to Pentoxifylline [101]. Romazarit (Ro-31-3948) derived from oxazole and isoxazole propionic acids has been shown to block IL- 1-induced activation of human fibroblasts in vitro and in animal models reduces inflammation [102,103,104]. By using a spontaneous autoimmune MRL/lpr mouse model, a significant efficacy was shown [105]. Two-dimensional structures of some of these molecules are shown in Figure 14. 

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