Biology Reference
In-Depth Information
cellular proteins that interact with purine-containing compounds, cross-reaction
is always a consideration, and detection of such unintended interactions can be
challenging. Moreover, PDE inhibitors whose structures or components of these
structures that do not mimic the purine in cNs have also been found to interact with
non-PDE cellular proteins. When possible, employing several PDE inhibitors with
different structures in a study significantly strengthens the validity of the interpre-
tations. Concepts based on biochemical results associated with use of one inhibitor
may need to be revisited if other interactions are subsequently found (Ohshiro et al.
2008
; Taniguchi et al.
2006
; Thompson
1991
).
4.1
Interaction with Multiple PDEs
Recently, consideration has been given to the potential clinical advantages of
combining administration of compounds that are selective for different PDEs,
utilizing compounds that inhibit two PDEs, that is, dual-selective compounds, or
use of more nonselective compounds that inhibit different PDEs (Giembycz
2006
).
For instance, inhibitors that block either PDE5 or PDE1 appear to impede patho-
logical remodeling in vascular smooth muscle and cardiac tissue, although the
relative roles of these PDEs is yet to be determined (Kang et al.
2003
; Kass et al.
2007
; Kim et al.
2001
; Miller et al.
2009
; Rybalkin et al.
1997
,
2003
; Takimoto
et al.
2005a
; Zhu and Strada
2007
). However, the potential to combine selective
inhibitors for both PDE families as a therapy to block the remodeling merits further
study. The rationale for the use of either dual-selective or nonselective inhibitors is
that relatively low concentration of such an inhibitor could partially block several
PDEs, for example, PDE5/PDE1, PDE4/PDE1, PDE4/PDE3, etc. in a given tissue,
to produce significant increases in cNs. In contrast to the concept described above
of nearly absolute specificity of a particular PDE to control cAMP or cGMP in
a particular locale, this approach assumes that at least in some situations multiple
PDEs work jointly to affect cN concentrations. The hypothesis suggests that
moderate blockage of several PDEs might produce modest, but physiologically
relevant, changes in cN without incurring the adverse effects commonly associated
with more marked changes in cN in either the target or the nontarget tissues when
a specific inhibitor more completely blocks a particular PDE (Giembycz
2006
).
This is conceptually similar to the potential advantages of partial inhibition of
a particular PDE described above (Burgin et al.
2010
).
4.2
Interaction with Other Proteins in the cN-Signaling Pathway
Use of compounds designed to block PDE action as well as activating other proteins
in the cN-signaling pathway is also worthy of consideration. cN analogs commonly
function not only as activators of particular cN-dependent protein kinases, cN-gated
channels, or EPACs, but also as inhibitors of certain PDEs; many cN analogs are
