Phosphodiesterase inhibitor

Phosphodiesterase-5

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 PDE 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

PDE3 selective inhibitors

PDE3 is sometimes referred to as cGMP-inhibited phosphodiesterase.

PDE4 selective inhibitors

PDE4 inhibitors

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.; Weiss B. (1972). "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. PMID 4342220. doi:10.1016/0005-2744(72)90060-5.
  2. Weiss B (1975). "Differential activation and inhibition of the multiple forms of cyclic nucleotide phosphodiesterase". Adv. Cycl. Nucl. Res. 5: 195–211.
  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.; Hait W.N. (1977). "Selective cyclic nucleotide phosphodiesterase inhibitors as potential therapeutic agents". Annu. Rev. Pharmacol. Toxicol. 17: 441–477. PMID 17360. doi:10.1146/annurev.pa.17.040177.002301.
  5. 1 2 Essayan DM. (2001). "Cyclic nucleotide phosphodiesterases.". The Journal of Allergy and Clinical Immunology. 108 (5): 671–80. PMID 11692087. doi:10.1067/mai.2001.119555.
  6. 1 2 Deree J, Martins JO, Melbostad H, Loomis WH, Coimbra R (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. PMC 2664230Freely accessible. PMID 18568240. doi:10.1590/S1807-59322008000300006.
  7. Marques LJ, Zheng L, Poulakis N, Guzman J, Costabel U (February 1999). "Pentoxifylline inhibits TNF-alpha production from human alveolar macrophages". Am. J. Respir. Crit. Care Med. 159 (2): 508–11. PMID 9927365. doi:10.1164/ajrccm.159.2.9804085.
  8. 1 2 Peters-Golden M, Canetti C, Mancuso P, Coffey MJ (2005). "Leukotrienes: underappreciated mediators of innate immune responses". Journal of Immunology. 174 (2): 589–94. PMID 15634873. doi:10.4049/jimmunol.174.2.589.
  9. Daly JW, Jacobson KA, Ukena D (1987). "Adenosine receptors: development of selective agonists and antagonists". Prog Clin Biol Res. 230 (1): 41–63. PMID 3588607.
  10. MacCorquodale, DW (July 1929). "THE SYNTHESIS OF SOME ALKYLXANTHINES". Journal of the American Chemical Society. 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 (July 1986). "Analogues of caffeine and theophylline: effect of structural alterations on affinity at adenosine receptors". Journal of Medicinal Chemistry. 29 (7): 1305–8. PMID 3806581. doi:10.1021/jm00157a035.
  14. Daly JW, Jacobson KA, Ukena D (1987). "Adenosine receptors: development of selective agonists and antagonists". Progress in Clinical and Biological Research. 230: 41–63. PMID 3588607.
  15. Choi OH, Shamim MT, Padgett WL, Daly JW (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. PMID 2456442. doi:10.1016/0024-3205(88)90517-6.
  16. Shamim MT, Ukena D, Padgett WL, Daly JW (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. PMID 2724296. doi:10.1021/jm00126a014.
  17. Daly JW, Hide I, Müller CE, Shamim M (1991). "Caffeine analogs: structure-activity relationships at adenosine receptors". Pharmacology. 42 (6): 309–21. PMID 1658821. doi:10.1159/000138813.
  18. Ukena D, Schudt C, Sybrecht GW (February 1993). "Adenosine receptor-blocking xanthines as inhibitors of phosphodiesterase isozymes". Biochemical Pharmacology. 45 (4): 847–51. PMID 7680859. doi:10.1016/0006-2952(93)90168-V.
  19. Daly JW (July 2000). "Alkylxanthines as research tools". Journal of the Autonomic Nervous System. 81 (1–3): 44–52. PMID 10869699. doi:10.1016/S0165-1838(00)00110-7.
  20. Daly JW (August 2007). "Caffeine analogs: biomedical impact". Cellular and Molecular Life Sciences : CMLS. 64 (16): 2153–69. PMID 17514358. doi:10.1007/s00018-007-7051-9.
  21. González MP, Terán C, Teijeira M (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. PMID 17668454. doi:10.1002/med.20108.
  22. Baraldi PG, Tabrizi MA, Gessi S, Borea PA (January 2008). "Adenosine receptor antagonists: translating medicinal chemistry and pharmacology into clinical utility". Chemical Reviews. 108 (1): 238–63. PMID 18181659. doi:10.1021/cr0682195.
  23. Lim YH, Lee YY, Kim JH, Shin J, Lee JU, Kim KS, Kim SK, Kim JH, Lim HK (2010). "Development of acute myocardial infarction in a young female patient with essential thrombocythemia treated with anagrelide: a case report". Korean J Hematol. 45: 136–8. PMC 2983030Freely accessible. PMID 21120194. doi:10.5045/kjh.2010.45.2.136.
  24. de Visser YP, Walther FJ, Laghmani EH, van Wijngaarden S, Nieuwland K, Wagenaar GT (2008). "Phosphodiesterase-4 inhibition attenuates pulmonary inflammation in neonatal lung injury". Eur Respir J. 31 (3): 633–644. PMID 18094015. doi:10.1183/09031936.00071307.
  25. Yu MC, Chen JH, Lai CY, Han CY, Ko WC (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. PMID 19853596. doi:10.1016/j.ejphar.2009.10.031.
  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 (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): 26. PMID 3063534. doi:10.1007/BF00381071.
  28. 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. doi:10.1016/j.neuroscience.2004.07.038.
  29. Kanes SJ, Tokarczyk J, Siegel SJ, Bilker W, Abel T, Kelly MP (2006). "Rolipram: A specific phosphodiesterase 4 inhibitor with potential antipsychotic activity". Neuroscience. 144 (1): 239–46. PMC 3313447Freely accessible. PMID 17081698. doi:10.1016/j.neuroscience.2006.09.026.
  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 (2009). "Sleep deprivation impairs cAMP signaling in the hippocampus". Nature. 461 (7267): 1122–1125. PMC 2783639Freely accessible. PMID 19847264. doi:10.1038/nature08488.
  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. PMID 22100138. doi:10.1016/j.ejmech.2011.10.040.
  34. Weber M, Breier M, Ko D, Thangaraj N, Marzan DE, Swerdlow NR (May 2009). "Evaluating the antipsychotic profile of the preferential PDE10A inhibitor, papaverine". Psychopharmacology (Berl.). 203: 723–35. PMC 2748940Freely accessible. PMID 19066855. doi:10.1007/s00213-008-1419-x.
  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". Life Sciences. 10: 133–144. doi:10.1016/0024-3205(71)90086-5.
  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
This article is issued from Wikipedia. The text is licensed under Creative Commons - Attribution - Sharealike. Additional terms may apply for the media files.