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Phosphodiesterase inhibitor

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Title: Phosphodiesterase inhibitor  
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Phosphodiesterase inhibitor

A phosphodiesterase inhibitor is a drug that blocks one or more of the five subtypes of the enzyme phosphodiesterase (PDE), thereby 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 1972[1] and were soon afterward shown to be selectively inhibited in the brain and in other tissues by a variety of drugs.[2][3] The potential for selective phosphodiesterase 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

Nonselective phosphodiesterase inhibitors

Methylated xanthines and derivatives:[5]

Methylated xanthines act as both

  1. competitive nonselective phosphodiesterase inhibitors,[5] which raise intracellular cAMP, activate PKA, inhibit TNF-alpha [6][7] and leukotriene [8] synthesis, and reduce inflammation and innate immunity [8] and
  2. nonselective adenosine receptor antagonists [9]

But different analogues show varying potency at the numerous subtypes, and a wide range of synthetic xanthine derivatives (some nonmethylated) have been developed in the search for compounds with greater selectivity for phosphodiesterase enzyme or adenosine receptor subtypes.[10][11][12][13][14][15][16][17][18][19][20][21][22]

PDE1 selective inhibitors

PDE2 selective inhibitors

  • EHNA (erythro-9-(2-hydroxy-3-nonyl)adenine)
  • BAY 60-7550 (2-[(3,4-dimethoxyphenyl)methyl]-7-[(1R)-1-hydroxyethyl]-4-phenylbutyl]-5-methyl-imidazo[5,1-f][1,2,4]triazin-4(1H)-one)
  • Oxindole
  • PDP (9-(6-Phenyl-2-oxohex-3-yl)-2-(3,4-dimethoxybenzyl)-purin-6-one)

PDE3 selective inhibitors

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.
  • Piclamilast, a more potent inhibitor than rolipram.[24]
  • Luteolin, supplement extracted from peanuts that also possesses IGF-1 properties.[25]
  • Drotaverine, used to alleviate renal colic pain, also to hasten cervical dilatation in labor
  • Roflumilast, indicated for people with severe COPD to prevent symptoms such as coughing and excess mucus from worsening[26]

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[27] and have also recently been proposed for use as antipsychotics.[28][29]

On October 26, 2009, The University of Pennsylvania reported that researchers at their institution had discovered a link between elevated levels of PDE4 (and therefore decreased levels of cAMP) in sleep deprived mice. Treatment with a PDE4 inhibitor raised the deficient cAMP levels and restored some functionality to Hippocampus-based memory functions.[30]

PDE5 selective inhibitors

PDE7 selective inhibitors

Recent studies have shown quinazoline type PDE7 inhibitor to be potent anti-inflammatory and neuroprotective agents.[33]

PDE10 selective inhibitors

Papaverine, an opium alkaloid, has been reported to act as a PDE10 inhibitor.[34][35][36] PDE10A is almost exclusively expressed in the striatum and subsequent increase in cAMP and cGMP after PDE10A inhibition (e.g. by papaverine) is "a novel therapeutic avenue in the discovery of antipsychotics".[37]

References

  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. ^ a b Essayan DM. (2001). "Cyclic nucleotide phosphodiesterases.". The Journal of Allergy and Clinical Immunology 108 (5): 671–80.  
  6. ^ a b Deree J, Martins JO, Melbostad H, Loomis WH, Coimbra R.; Martins; Melbostad; Loomis; Coimbra (2008). "Insights into the Regulation of TNF-α Production in Human Mononuclear Cells: The Effects of Non-Specific Phosphodiesterase Inhibition". Clinics (Sao Paulo). 63 (3): 321–8.  
  7. ^ Marques LJ, Zheng L, Poulakis N, Guzman J, Costabel U; Zheng; Poulakis; Guzman; Costabel (February 1999). "Pentoxifylline inhibits TNF-alpha production from human alveolar macrophages". Am. J. Respir. Crit. Care Med. 159 (2): 508–11.  
  8. ^ a b Peters-Golden M, Canetti C, Mancuso P, Coffey MJ.; Canetti; Mancuso; Coffey (2005). "Leukotrienes: underappreciated mediators of innate immune responses". Journal of Immunology 174 (2): 589–94.  
  9. ^ Daly JW, Jacobson KA, Ukena D.; Jacobson; Ukena (1987). "Adenosine receptors: development of selective agonists and antagonists". Prog Clin Biol Res. 230 (1): 41–63.  
  10. ^ MacCorquodale DW. THE SYNTHESIS OF SOME ALKYLXANTHINES. Journal of the American Chemical Society. 1929 July;51(7) 2245–2251. doi:10.1021/ja01382a042
  11. ^ WO patent 1985002540, Sunshine A, Laska EM, Siegel CE, "ANALGESIC AND ANTI-INFLAMMATORY COMPOSITIONS COMPRISING XANTHINES AND METHODS OF USING SAME", granted 1989-03-22 , assigned to RICHARDSON-VICKS, INC.
  12. ^ Constantin Koulbanis, Claude Bouillon, Patrick Darmenton,"Cosmetic compositions having a slimming action", US patent 4288433, granted 1981-09-04 , assigned to L'Oreal 
  13. ^ Daly JW, Padgett WL, Shamim MT; Padgett; Shamim (July 1986). "Analogues of caffeine and theophylline: effect of structural alterations on affinity at adenosine receptors". Journal of Medicinal Chemistry 29 (7): 1305–8.  
  14. ^ Daly JW, Jacobson KA, Ukena D; Jacobson; Ukena (1987). "Adenosine receptors: development of selective agonists and antagonists". Progress in Clinical and Biological Research 230: 41–63.  
  15. ^ Choi OH, Shamim MT, Padgett WL, Daly JW; Shamim; Padgett; Daly (1988). "Caffeine and theophylline analogues: correlation of behavioral effects with activity as adenosine receptor antagonists and as phosphodiesterase inhibitors". Life Sciences 43 (5): 387–98.  
  16. ^ Shamim MT, Ukena D, Padgett WL, Daly JW; Ukena; Padgett; Daly (June 1989). "Effects of 8-phenyl and 8-cycloalkyl substituents on the activity of mono-, di-, and trisubstituted alkylxanthines with substitution at the 1-, 3-, and 7-positions". Journal of Medicinal Chemistry 32 (6): 1231–7.  
  17. ^ Daly JW, Hide I, Müller CE, Shamim M; Hide; Müller; Shamim (1991). "Caffeine analogs: structure-activity relationships at adenosine receptors". Pharmacology 42 (6): 309–21.  
  18. ^ Ukena D, Schudt C, Sybrecht GW; Schudt; Sybrecht (February 1993). "Adenosine receptor-blocking xanthines as inhibitors of phosphodiesterase isozymes".  
  19. ^ Daly JW (July 2000). "Alkylxanthines as research tools". Journal of the Autonomic Nervous System 81 (1–3): 44–52.  
  20. ^ Daly JW (August 2007). "Caffeine analogs: biomedical impact". Cellular and Molecular Life Sciences : CMLS 64 (16): 2153–69.  
  21. ^ González MP, Terán C, Teijeira M; Terán; Teijeira (May 2008). "Search for new antagonist ligands for adenosine receptors from QSAR point of view. How close are we?". Medicinal Research Reviews 28 (3): 329–71.  
  22. ^ Baraldi PG, Tabrizi MA, Gessi S, Borea PA; Tabrizi; Gessi; Borea (January 2008). "Adenosine receptor antagonists: translating medicinal chemistry and pharmacology into clinical utility". Chemical Reviews 108 (1): 238–63.  
  23. ^ http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2983030/?tool=pubmed
  24. ^ de Visser YP, Walther FJ, Laghmani EH, van Wijngaarden S, Nieuwland K, Wagenaar GT.; Walther; Laghmani; Van Wijngaarden; Nieuwland; Wagenaar (2008). "Phosphodiesterase-4 inhibition attenuates pulmonary inflammation in neonatal lung injury". Eur Respir J 31 (3): 633–644.  
  25. ^ Yu MC, Chen JH, Lai CY, Han CY, Ko WC.; Chen; Lai; Han; Ko (2009). "Luteolin, a non-selective competitive inhibitor of phosphodiesterases 1-5, displaced [(3)H]-rolipram from high-affinity rolipram binding sites and reversed xylazine/ketamine-induced anesthesia". Eur J Pharmacol. 627 (1–3): 269–75.  
  26. ^ http://pharmacistsociety.skipta.com/article.aspx/o/4c18ca7f-1da9-4587-b304-64014e651663/09b6025d-60a0-4657-8b3f-b78ffc8f6f1c
  27. ^ 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.; Breulet; Gerard-Vandenhove; Guiot-Goffioul; Plomteux; Sastre-y-Hernández; Schratzer; Troisfontaines; von Frenckell; Wachtel (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.  
  28. ^ Maxwell CR, Kanes SJ, Abel T, Siegel SJ.; Kanes; Abel; Siegel (2004). "Phosphodiesterase inhibitors: a novel mechanism for receptor-independent antipsychotic medications". Neuroscience. 129 (1): 101–7.  
  29. ^ Kanes SJ, Tokarczyk J, Siegel SJ, Bilker W, Abel T, Kelly MP.; Tokarczyk; Siegel; Bilker; Abel; Kelly (2006). "Rolipram: A specific phosphodiesterase 4 inhibitor with potential antipsychotic activity". Neuroscience. 144 (1): 239–46.  
  30. ^ Vecsey CG, Baillie GS, Jaganath D, Havekes R, Daniels A, Wimmer M, Huang T, Brown KM, Li XY, Descalzi G, Kim SS, Chen T, Shang YZ, Zhuo M, Houslay MD, Abel T.; Baillie; Jaganath; Havekes; Daniels; Wimmer; Huang; Brown; Li; Descalzi; Kim; Chen; Shang; Zhuo; Houslay; Abel (2009). "Sleep deprivation impairs cAMP signaling in the hippocampus". Nature. 461 (7267): 1122–1125.  
  31. ^ http://vigrarx.com/ordernow.php
  32. ^ http://www.mdidea.com/products/new/new03804.html
  33. ^ Redondo, M.; Zarruk, JG.; Ceballos, P.; Pérez, DI.; Pérez, C.; Perez-Castillo, A.; Moro, MA.; Brea, J. et al. (Jan 2012). "Neuroprotective efficacy of quinazoline type phosphodiesterase 7 inhibitors in cellular cultures and experimental stroke model". Eur J Med Chem 47 (1): 175–85.  
  34. ^ Evaluating the antipsychotic profile of the preferential PDE10A inhibitor, papaverine; M. Weber, M. Breier, D. Ko, N. Thangaraj, D. E. Marzan, and N. R. Swerdlow, Department of Psychiatry, UCSD School of Medicine, 9500 Gilman Dr., La Jolla, CA 92093-0804,USA; http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2748940/pdf/nihms119431.pdf
  35. ^ Inhibitory Mechanism of Papaverine on Carbachol-Induced Contraction in Bovine Trachea; Takeharu Kaneda1,*, Yukako Takeuchi1, Hirozumi Matsui1, Kazumasa Shimizu1, Norimoto Urakawa1,and Shinjiro Nakajyo, Division of Veterinary Pharmacology, Nippon Veterinary and Animal Science University; http://www.jstage.jst.go.jp/article/jphs/98/3/275/_pdf
  36. ^ Papaverine - induced inhibition of phosphodiesterase activity in various mammalian tissues, G. Pöch and W. R. Kukovetz, Department of Pharmacology, University of Graz, A-8010, Graz, Austria; http://www.sciencedirect.com/science/article/pii/0024320571900865
  37. ^ Effects of phosphodiesterase 10 inhibition on striatal cyclic AMP and peripheral physiology in rats; An Torremans, Abdellah Ahnaou, An Van Hemelrijck, Roel Straetemans, Helena Geys, Greet Vanhoof, Theo F. Meert, and Wilhelmus H. Drinkenburg; http://www.ane.pl/pdf/7002.pdf
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