D. PDE6 inhibitor pharmacology

The rational design of more specific PDE5 inhibitors for the treatment of erectile dysfunction, pulmonary hypertension, and potentially other disease states requires a more detailed understanding of the molecular architecture of the catalytic site of rod and cone PDE6. This is because most PDE5 inhibitors [with the notable exception of tadalafil (Cialis)] cannot discriminate PDE5 from PDE6. Indeed, a well-documented side effect of Viagra usage is a transient disturbance of visual function (Goldstein et al., 1998).

PDE5 is the most closely related PDE to the photoreceptor PDE6, based on several additional criteria: (1) amino acid sequence, (2) 3-D molecular organization, (3) substrate specificity, (4) cGMP binding properties(Cote, 2004). However, there are also notable differences that set apart PDE6, particularly its high catalytic efficiency and its regulation by a low molecular weight γ subunit.

We hypothesize that differences in the substrate and drug binding sites in the catalytic pocket of PDE5, rod PDE6, and cone PDE6 can be identified by a combination of structural homology modeling and pharmacological approaches.

References

Cote,R.H. (2004). Characteristics of photoreceptor PDE (PDE6): similarities and differences to PDE5. International Journal of Impotence Research in press.

Goldstein,I., Lue,T.F., Padma-Nathan,H., Rosen,R.C., Steers,W.D., Wicker,P.A., and Sildenafil Study Group (1998). Oral sildenafil in the treatment of erectile dysfunction. N. Engl. J. Med. 338, 1397-1404.