How Viagra Works Sildenofil (5-[2-ethoxy-5- (4-methylpiperazin-1- ylsulfonyl) phenyl]-1- methyl-3-propyl-1,6dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-one) is better known as its citrate

salt, Viagra. Viagra is most often used in the treatment of erectile dysfunction. The way it works is to inhibit a specific enzyme called phosphodiesterase-5 located in the smooth muscle of the arteries that supply blood to the penis. In order to understand the significance of this inhibition, we need a little background. Nitric oxide (NO) is a chemical produced by special nerve cells called NANC nerve cells. (NANC stands for nonadrenergic-noncholinergic.) Under certain, rather special, conditions the brain sends a signal down the axon of a NANC nerve cell located in the penis. This causes NO to be released into the blood stream in the arteries of the penis. One of the main roles of NO is to trigger the relaxation of the smooth muscle that lines the arteries. This leads to vasodilation and the lowering of blood pressure. In the penis this causes engorgement as the arteries expand and fill up with blood. The result is an erection that's stimulated by NO. Nitric oxide acts locally. It diffuses into adjacent cells and binds to an enzyme called guanylyl cyclase. The binding of NO activates the enzyme, stimulating it to produce cyclic guanosine monophosphate or cGMP. The substrate for this reaction is guanosine triphosphate (GTP), a molecule that's similar to ATP except that the base is guanine instead of adenine. ATP can be also be cyclized to form cAMPa compound analogous to cGMP. cAMP is a common signal in many hormone-induced signal transduction pathways (and in creating a sense of smell). Like cAMP, cGMP is a signalling molecule. It activates specific enzymes that add phosphate to various proteins causing them to become more, or perhaps less, active. During an erection, the cGMP signal leads to changes in phosphorylation of muscle proteins causing the muscles to relax and the arteries to expand. This production of NO requires the attention of the brain, which has to keep focused on the task at hand. As you might expect, cGMP is not infinitely stable; otherwise a man might have an erection forever. cGMP is removed by the action of cGMP phosphodiesterase, which converts it to GMP. The turnover of cGMP in the penis is quite rapid leading to lack of signal unless NO is continually produced by the NANC nerve cells in order to replenish the supply of cGMP by reactivating guanylyl cyclase. The smooth muscle cells in the penis contain a special cGMP phosphodiesterase called phosphodiesterase-5 (PDE5). Sometimes the degradation of cGMP by PDE5 outpaces the production of cGMP by guanylyl cyclase. In such cases, the steady-state levels of cGMP aren't sufficient to signal muscle relaxation and no erection occurs. This is a common cause of erectile disfunction. Viagra works by inhibiting PDE5 thus blocking the breakdown of cGMP. This causes levels of cGMP to increase and an erection is prolonged. The structure of the PDE5 enzyme has been solved by Sung et al. (2003) in the presence of bound sildenafil (Viagra) and two

other inhibitors, tadalafil (Cialis) and vardenafil (Levitra). The structures are shown as stereo images in the figure below.

Viagra (sildenafil): Pfizer (approved by the FDA = March 27, 1998) Cialis (tadalafil): Eli Lilly and ICOS (approved by the FDA = November 1, 2003) Levitra (vardenafil): GlaxoSmithKline and Bayer (approved by the FDA = August 20, 2003)

The upper image is the PDE5 protein with overlapping molecules of sildenafil (red) and tadalfil (green) bound to the enzyme. The bottom images show the structures of the three inhibitors. Viagra binds to the site where cGMP would normally bind, thus blocking the degradation of cGMP. The structure of Viagra is similar to cGMP and this explains why it is such a potent inhibitor. Reference: Sung B-J., Hwang, K.Y., Jeon, Y.H., Lee, J.I., Heo, Y.S., Kim, J.H., Moon, J., Yoon, J.M., Hyun, Y.L., Kim, E., Eum, S.J., Park, S.Y., Lee, J.O., Lee, T.G., Ro, S., and Cho, J.M. (2003) Structure of the catalytic domain of human phosphodiesterase 5 with bound drug molecules. Nature 425:98-102.