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Phosphodiesterase inhibitors
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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).
History
The different forms or subtypes of phosphodiesterase were initially isolated from rat brains by Uzunov and Weiss in 19721 and were soon afterwards shown to be selectively inhibited in the brain and in other tissues by a variety of drugs.23 The potential for selective phosphodisterase inhibitors as therapeutic agents was predicted as early as 1977 by Weiss and Hait.4 This prediction meanwhile has proved to be true in a variety of fields.
Classification
Non-selective phosphodiesterase inhibitors
PDE1 selective inhibitors
PDE2 selective inhibitors
- EHNA (erythro-9-(2-hydroxy-3-nonyl)adenine)
PDE3 selective inhibitors
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Main article: PDE3 inhibitor
PDE3 is sometimes referred to as cGMP-inhibited phosphodiesterase.
PDE4 selective inhibitors
- Mesembrine, an alkaloid from the herb Sceletium tortuosum
- 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.
- Pentoxifylline, a drug that potentially enhances circulation and may have applicability in treatment of diabetes, fibrotic disorders, peripheral nerve damage, and microvascular injuries
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 effects5 and have also recently been proposed for use as antipsychotics.67
PDE5 selective inhibitors
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Main article: PDE5 inhibitor
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.
- ^ Bobon D, Breulet M, Gerard-Vandenhove MA, Guiot-Goffioul F, Plomteux G, Sastre-y-Hernandez M, Schratzer M, Troisfontaines B, von Frenckell R, Wachtel H. (1988). "Is phosphodiesterase inhibition a new mechanism of antidepressant action? A double blind double-dummy study between rolipram and desipramine in hospitalized major and/or endogenous depressives.". Eur Arch Psychiatry Neurol Sci. 238 (1): 2–6. PMID 3063534.
- ^ Maxwell CR, Kanes SJ, Abel T, Siegel SJ. (2004). "Phosphodiesterase inhibitors: a novel mechanism for receptor-independent antipsychotic medications.". Neuroscience. 129 (1): 101–7. doi:10.1016/j.neuroscience.2004.07.038. PMID 15489033.
- ^ Kanes SJ, Tokarczyk J, Siegel SJ, Bilker W, Abel T, Kelly MP. (2006). "Rolipram: A specific phosphodiesterase 4 inhibitor with potential antipsychotic activity.". Neuroscience. ? (?): ?. PMID 17081698.
