A phosphodiesterase inhibitor is a drug that blocks one or more of the five subtypes of the enzyme phosphodiesterase, thereby preventing the inactivation of the intracellular second messengers cyclic adenosine monophosphate and cyclic guanosine monophosphate by the respective PDE subtype. The ubiquitous presence of this enzyme means that non-specific inhibitors have a wide range of actions, the actions in the heart, and lungs being some of the first to find a therapeutic use.
History
The different forms or subtypes of phosphodiesterase were initially isolated from rat brains in the early 1970s and were soon afterward shown to be selectively inhibited in the brain and in other tissues by a variety of drugs. The potential for selective phosphodiesterase inhibitors as therapeutic agents was predicted as early as 1977 by Weiss and Hait. This prediction meanwhile has proved to be true in a variety of fields.
IBMX, used as investigative tool in pharmacological research
paraxanthine
pentoxifylline, a drug that has the potential to enhance circulation and may have applicability in treatment of diabetes, fibrotic disorders, peripheral nerve damage, and microvascular injuries
Rolipram, used as investigative tool in pharmacological research
Ibudilast, a neuroprotective and bronchodilator drug used mainly in the treatment of asthma and stroke. It inhibits PDE4 to the greatest extent, but also shows significant inhibition of other PDE subtypes, and so acts as a selective PDE4 inhibitor or a non-selective phosphodiesterase inhibitor, depending on the dose.
Piclamilast, a more potent inhibitor than rolipram.
Luteolin, supplement extracted from peanuts that also possesses IGF-1 properties.
PDE4 is the major cAMP-metabolizing enzyme found in inflammatory and immune cells. PDE4 inhibitors have proven potential as anti-inflammatory drugs, especially in inflammatory pulmonary diseases such as asthma, COPD, and rhinitis. They suppress the release of cytokines and other inflammatory signals, and inhibit the production of reactive oxygen species. PDE4 inhibitors may have antidepressive effects and have also recently been proposed for use as antipsychotics. On October 26, 2009, The University of Pennsylvania reported that researchers at their institution had discovered a link between elevated levels of PDE4 in sleep deprived mice. Treatment with a PDE4 inhibitor raised the deficient cAMP levels and restored some functionality to Hippocampus-based memory functions.
Sildenafil, tadalafil, vardenafil, and the newer udenafil and avanafil selectively inhibit PDE5, which is cGMP-specific and responsible for the degradation of cGMP in the corpus cavernosum. These phosphodiesterase inhibitors are used primarily as remedies for erectile dysfunction, as well as having some other medical applications such as treatment of pulmonary hypertension.
Dipyridamole also inhibits PDE5. This results in added benefit when given together with NO or statins.
PDE7 selective inhibitors
Recent studies have shown Quinazoline type PDE7 inhibitor to be potent anti-inflammatory and neuroprotective agents.
PDE9 selective inhibitors
, the main metabolite of Caffeine, is another cGMP-specific phosphodiesterase inhibitor which inhibits PDE9, a cGMP preferring phosphodiesterase. PDE9 is expressed as high as PDE5 in the corpus cavernosum.
PDE10 selective inhibitors
, an opium alkaloid, has been reported to act as a PDE10 inhibitor. PDE10A is almost exclusively expressed in the striatum and subsequent increase in cAMP and cGMP after PDE10A inhibition is "a novel therapeutic avenue in the discovery of antipsychotics".
