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PDE isoenzyme

Constitutive activity of PDE was found in cultured carrot cells this activity did not depend on either Ca2+ or CAM. By contrast, a CAM-dependent isoform of PDE (CAM-PDE) was induced in the cells by adding forskolin or Bt2cAMP to the culture [30]. Induction of CAM-PDE activity in Bt2cAMP-treated carrot cells was markedly inhibited in the presence of verapamil, and addition of Ca2+-ionophore A23187 induced CAM-PDE [34]. These results suggest that increased Ca2+, but not cAMP, in the stimulated carrot cells triggers induction of the PDE isoenzyme. Affinity of CAM-PDE to the substrate was low compared to constitutive PDE Km values, 0.14 and 0.07 pM, respectively) however, V for the induced PDE was approximately 2.7 times higher than for the constitutive isoenzyme. [Pg.490]

The second messenger molecules Ca2+ and cyclic AMP (cAMP) provide major routes for controlling cellular functions. In many instances, calcium (Ca2+) achieves its intracellular effects by binding to the receptor protein calmodulin. Calmodulin has the ability to associate with and modulate different proteins in a Ca2+-dependent and reversible manner. Calmodulin-dependent cyclic nucleotide phosphodiesterase (CaMPDE, EC 3.1.4.17) is one of the key enzymes involved in the complex interactions that occur between the cyclic-nucleotide and Ca2+ second messenger systems (see Figure 13.2). CaMPDE exists in different isozymic forms, which exhibit distinct molecular and catalytic properties. The differential expression and regulation of individual phosphodiesterase (PDE) isoenzymes in different tissues relates to their function in the body. [Pg.175]

There is now an ongoing interest to develop highly selective inhibitors also against certain other phosphodiesterases, because general structure-activity relationships can be transferred from one PDE isoenzyme to others [37]. [Pg.65]

Hetero-Diels-Alder reactions have been extensively used in organic synthesis. Cycloadditions of imines 184 with maleimide 185 (Scheme 34) generated pyrazo-lopyridines 186 [71]. These compounds were further elaborated as shown in Scheme 34 to provide pyrazolopyridopyridazines 187 which were potent and selective PDE5 inhibitors [72]. Compound 188 was selected for further evaluation. This compound had superior selectivity towards other PDE isoenzymes and was found to be efficacious in an anesthetized rabbit model of erectile function. [Pg.268]

CDP840 is a selective inhibitor of the PDE-IV isoenzyme and interest in the compound arises from its potential application as an antiasthmatic agent. Chemists at Merck Co. used the asymmetric epoxidation reaction to set the stereochemistry of the carbon framework and subsequently removed the newly established C-O bonds." Epoxidation of the trisubstituted olefin 51 provided the desired epoxide in 89% ee and in 58% yield. Reduction of both C-O bonds was then accomplished to provide CDP840. [Pg.41]

Phosphodiesterases are a group of enzymes that, among other actions, hydrolyse cAMP. Phosphodiesterase inhibitors are selective for phosphodiesterase III (PDE-III) isoenzyme present in the heart. They prevent the degradation of cAMP, thereby increasing its intracellular concentration (Figure 8.4). This leads to an increase in the intracellular concentration of Ca2+ and an increased contractility and heart rate. PDE-III inhibitors have no adrenoceptor agonistic activity and therefore can be used in combination with other sympathomimetic drugs. They also increase cAMP levels in vascular smooth muscle, but this results in lower intracellular Ca2+ concentrations and thus vasodilatation. [Pg.155]

Today 11 members of the human PDE superfamily are known, all of which are class I phosphodiesterases and all of which are intracellular or membrane-bound enzymes. Several of the isoenzymes are encoded by more than one gene which, in combination with the presence of different splice variants, brings the number of different PDE proteins to well over 50. The different isoenzymes are characterized according to their substrate specificity, sequence homology, kinetic properties, and sensitivity to certain known PDE inhibitors. Table 9.1 shows these properties together with the predominant tissue expression of the various PDEs. [Pg.244]


See other pages where PDE isoenzyme is mentioned: [Pg.243]    [Pg.244]    [Pg.244]    [Pg.245]    [Pg.248]    [Pg.529]    [Pg.374]    [Pg.2039]    [Pg.206]    [Pg.243]    [Pg.244]    [Pg.244]    [Pg.245]    [Pg.248]    [Pg.529]    [Pg.374]    [Pg.2039]    [Pg.206]    [Pg.589]    [Pg.417]    [Pg.246]    [Pg.248]    [Pg.259]    [Pg.279]    [Pg.280]    [Pg.545]    [Pg.446]    [Pg.575]    [Pg.74]   
See also in sourсe #XX -- [ Pg.490 ]




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PDEs isoenzymes

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