Biology Reference
In-Depth Information
pathway (Jeon et al.
2010
). Finally, EHNA, a selective and weak inhibitor of PDE2,
also inhibits adenosine deaminase (Mery et al.
1995
), which complicates its use in
biochemical studies.
5 Concluding Remarks
Major advances have been made in recent years in defining the physical and
chemical characteristics of the catalytic sites of PDEs and identifying improved
strategies for development of potent and selective inhibitors of the various PDE
families. X-ray crystallographic structures of the catalytic domains of numerous
PDEs has allowed for precise spatial considerations for future design of more
selective inhibitors. More recently, the X-ray crystal structures of regulatory
domains of these proteins have become available and provide new opportunities
for development of PDE inhibitors. The clinical success of the PDE5 inhibitors has
been a major advance in understanding the medical implications of these types of
drugs. Despite the availability of some selective PDE inhibitors, it is clear that great
caution is warranted when using these compounds. There are now well-documented
examples in which a PDE inhibitor that was considered to specifically target a
particular PDE has mechanisms of action that are unrelated to inhibition of PDE
activity. In addition, interpretation of results based on the concentration of a
“selective” inhibitor that is applied extracellularly is particularly problematic
since it is not possible to discern the concentration of that compound in the
intracellular milieu or in particular cellular compartments where it might reach
concentrations sufficient for inhibition of other PDEs. Use of several inhibitors and
a variety of approaches is important to validate interpretation of results in such
studies. Innovative strategies are needed to generate new inhibitors that are selec-
tive for specific PDE families and their subfamilies since these compounds are
greatly needed for investigational purposes that will hopefully lead to clinical use.
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