Inhibition of cyclic GMP-binding cyclic GMP-specific phosphodiesterase (Type 5) by sildenafil and related compounds.

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