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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).

HistoryEdit

These multiple forms or subtypes of phosphodiesterase were initially isolated from rat brain by Uzunov and Weiss in 1972[1] and were soon afterward shown to be selectively inhibited by a variety of drugs in brain and other tissues. [2][3] The potential for selective phosphodisterase inhibitors to be used as therapeutic agents was predicted as early as 1977 by Weiss and Hait.[4] This prediction has now come to pass in a variety of fields.

ClassificationEdit

Non-selective phosphodiesterase inhibitorsEdit

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

PDE1-selective inhibitorsEdit

  1. Vinpocetine

PDE2-selective inhibitorsEdit

  1. EHNA

PDE3-selective inhibitorsEdit

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

PDE4-selective inhibitorsEdit

  1. Mesembrine: an alkaloid present in the herb Sceletium tortuosum
  2. Rolipram: used as investigative tool in pharmacological research
  3. Ibudilast, a neuroprotective and bronchodilator drug used mainly in the treatment of asthma and stroke, inhibits PDE-4 to the greatest extent, but also shows significant inhibition of other PDE subtypes, and so can be viewed either as a selective PDE-4 inhibitor or a non-selective phosphodiesterase inhibitor depending on the dose used.

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[5] and have also recently been proposed for use as antipsychotic medications.[6][7]

PDE5-selective inhibitorsEdit

  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 primarily as remedies for erectile dysfunction, as well as having some other medical applications such as treatment of pulmonary hypertension.


ReferencesEdit

  1. 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.
  2. Weiss, B.: Differential activation and inhibition of the multiple forms of cyclic nucleotide phosphodiesterase. Adv. Cycl. Nucl. Res. 5:195-211, 1975.
  3. Fertel, R. and Weiss, B.: Properties and drug responsiveness of cyclic nucleotide phosphodiesterases of rat lung. Mol. Pharmacol. 12:678-687, 1976.
  4. Weiss, B. and Hait, W.N.: Selective cyclic nucleotide phosphodiesterase inhibitors as potential therapeutic agents. Ann. Rev. Pharmacol. Toxicol. 17:441-477, 1977.
  5. 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.
  6. Maxwell CR, Kanes SJ, Abel T, Siegel SJ. (2004). Phosphodiesterase inhibitors: a novel mechanism for receptor-independent antipsychotic medications.. Neuroscience. 129 (1): 101-7. PMID 15489033.
  7. 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.


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