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Vol. 56, Issue 1, 124-130, July 1999
Department of Molecular Physiology and Biophysics, Vanderbilt
University School of Medicine, Nashville, Tennessee (I.V.T., S.H.F.,
J.D.C.); and Department of Discovery Biology, Pfizer Central Research,
Sandwich, United Kingdom (S.A.B.)
The cGMP-binding cGMP-specific phosphodiesterase (PDE5) degrades cGMP
and regulates the intracellular level of cGMP in many tissues,
including the smooth muscle of the corpus cavernosum of the penis.
Sildenafil (Viagra), a specific PDE5 inhibitor, promotes penile
erection by blocking the activity of PDE5, which causes cGMP to
accumulate in the corpus cavernosum. In the present study, sildenafil,
like other PDE5 inhibitors, stimulates cGMP binding to the allosteric
sites of PDE5 by interacting at the catalytic site of this enzyme, but
the drug does not compete with cGMP for binding at the allosteric
sites. Both sildenafil and zaprinast are competitive inhibitors of
PDE5, and double-inhibition analysis shows that these two inhibitors
added together interact with the catalytic site of PDE5 in a mutually
exclusive manner. After site-directed mutagenesis of each of 23 conserved amino acid residues in the catalytic domain of PDE5, the
pattern of changes in the IC50 values for sildenafil or
UK-122764 is similar to that found for zaprinast. However, among the
three inhibitors, sildenafil exhibits the most similar pattern of
changes in the IC50 to that found for the affinity of cGMP,
implying similar interactions with the catalytic domain. This may
explain in part the stronger inhibitory potency of sildenafil for
wild-type PDE5 compared with the other inhibitors [sildenafil
(Ki = 1 nM) > UK-122764 (Ki = 5 nM) > zaprinast
(Ki = 130 nM)]. The affinity of each
of these inhibitors for PDE5 is much higher than that of cGMP itself (Km = 2000 nM). It is concluded that
residues such as Tyr602, His607,
His643, and Asp754 may form important
interactions for sildenafil in PDE5, but because these amino acids are
conserved in all mammalian PDEs, the selectivity and potency of
sildenafil is likely to be provided by a nonconserved residue or
residues in the PDE5 catalytic domain.
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