Signaling pathway complications

There are a variety of structural classes of compounds that are active against each phosphodiesterase, and evidence suggests that selective inhibitors of PDEs can be identified. The structural diversity of PDE inhibitors provides a multitude of opportunities for development of compounds with drug-like properties. Furthermore, phosphodiesterase inhibition, which avoids direct interaction of a compound with a cell surface or nuclear receptor, may circumvent some of the target selectivity issues that can complicate receptor-based therapeutic approaches. As noted above, the specific subcellular distribution of phosphodiesterase enzymes is a key feature of their ability to modulate intracellular signaling pathways. This localization of the enzyme may minimize non-specific target... 

Fig. 9.1 Schematic model depicting the key events which mediate diabetes-associated vascular complications. Diabetes/hyperglycemia augments the levels of vasoactive peptides including Ang II/ET-1 that enhance the generation of reactive oxygen species (ROS). ROS-induced activation of growth-promoting signaling pathways, such as PKC and MAPK, contributes to aberrant vascular functions.

Defining the role of each i-AR subtype in catecholamine signalling is complicated not only by the multiplicity of second messenger pathways coupled to aj-ARs, but also by the limited availability of subtype selective compounds. Molecular biological techniques and the development of subtype selective compotmds are now allowing us to clarify subtype pharmacology, tissue expression, and the individual roles of each subtype in cellular signalling. 

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