Phosphodiesterase inhibitor

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A phosphodiesterase inhibitor is a drug that blocks one or more of the five subtypes of the enzyme phosphodiesterase (PDE), therefore preventing the inactivation of the intracellular second messengers, cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP), by the respective PDE subtype(s). These multiple forms or subtypes of phosphodiesterase were initially isolated from rat brain by Uzunov and Weiss in 1972 and were soon afterward shown to be selectively inhibited by a variety of drugs in brain and other tissues (Weiss,1975; Fertel and Weiss, 1976). The potential for selective phosphodisterase inhibitors to be used as therapeutic agents was predicted as early as 1977 by Weiss and Hait. This prediction has now come to pass in a variety of fields.

• Non-selective phosphodiesterase inhibitors:

1. the minor stimulant caffeine,
2. the bronchodilator theophylline,
3. IBMX (3-isobutyl-1-methylxanthine): used as investigative tool in pharmacological research.

• PDE1-selective inhibitors:

1. Vinpocetine

• PDE2-selective inhibitors:

1. EHNA

• PDE3-selective inhibitors:

1. enoximone and milrinone: used clinically for short-term treatment of cardiac failure. Clinically these drugs mimic sympathetic stimulation and increase cardiac output.
   PDE3 is sometimes referred to as cGMP-inhibited phosphodiesterase.

• PDE4-selective inhibitors:

1. mesembrine: an alkaloid present in the herb, Sceletium tortuosum
2. rolipram: used as investigative tool in pharmacological research

PDE4 is the major cAMP-metabolizing enzyme found in inflammatory and immune cells. PDE4 inhibitors have proven potential as anti-inflammatory drugs especially in airway diseases. They suppress the release of inflammatory signals, e.g., cytokines, and inhibit the production of reactive oxygen species. PDE4 inhibitors have a high therapeutic and commercial potential as non-steroidal disease controllers in inflammatory airway diseases such as asthma, COPD and rhinitis. PDE4 inhibitors may have an antidepressant action^[1] and have also recently been proposed for use as antipsychotic medications.^[2][3]

• PDE5-selective inhibitors:

1. sildenafil, tadalafil and vardenafil; and the newer ones, 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 as remedies for erectile dysfunction.

[edit] References

Uzunov, P. and Weiss, B.: Separation of multiple molecular forms of cyclic adenosine 3',5'-monophosphate phosphodiesterase in rat cerebellum by polyacrylamide gel electrophoresis. Biochim. Biophys. Acta 284:220-226, 1972.

Weiss, B.: Differential activation and inhibition of the multiple forms of cyclic nucleotide phosphodiesterase. Adv. Cycl. Nucl. Res. 5:195-211, 1975.

Fertel, R. and Weiss, B.: Properties and drug responsiveness of cyclic nucleotide phosphodiesterases of rat lung. Mol. Pharmacol. 12:678-687, 1976.

Weiss, B. and Hait, W.N.: Selective cyclic nucleotide phosphodiesterase inhibitors as potential therapeutic agents. Ann. Rev. Pharmacol. Toxicol. 17:441-477, 1977.