Biology:Phosphodiesterase inhibitor

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Short description: Drug
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). The ubiquitous presence of this enzyme means that non-specific inhibitors have a wide range of actions, the actions in the heart, and lungs being some of the first to find a therapeutic use.

History

The different forms or subtypes of phosphodiesterase were initially isolated from rat brains in the early 1970s[1][2] and were soon afterward shown to be selectively inhibited in the brain and in other tissues by a variety of drugs.[3][4] The potential for selective phosphodiesterase inhibitors as therapeutic agents was predicted as early as 1977 by Weiss and Hait.[5] This prediction meanwhile has proved to be true in a variety of fields.

Classification

Nonselective PDE inhibitors

Methylated xanthines and derivatives:[6]

Methylated xanthines act as both

  1. competitive nonselective phosphodiesterase inhibitors,[6] which raise intracellular cAMP, activate PKA, inhibit TNF-alpha[7][8] and leukotriene[9] synthesis, and reduce inflammation and innate immunity[9] and
  2. nonselective adenosine receptor antagonists[10]

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.[11][12][13][14][15][16][17][18][19][20][21][22][23]

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

PDE4 inhibitors
  • Mesembrenone, 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.[25]
  • Luteolin, supplement extracted from peanuts that also possesses IGF-1 properties.[26]
  • 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[27]
  • Apremilast, used to treat psoriasis and psoriatic arthritis.
  • Crisaborole, used to treat atopic dermatitis.
  • Glaucine, an aporphine alkaloid, low-potency PDE4 inhibitor, calcium channel blocker, dopamine antagonist and 5-HT2A positive allosteric modulator, used as antitussive in Eastern Europe and Iceland.

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[28] and have also been proposed for use as antipsychotics.[29][30]

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.[31]

PDE5 selective inhibitors

PDE7 selective inhibitors

Recent studies have shown quinazoline type PDE7 inhibitor to be potent anti-inflammatory and neuroprotective agents.[32]

PDE9 selective inhibitors

Paraxanthine, the main metabolite of caffeine (84% in humans),[33] is another cGMP-specific phosphodiesterase inhibitor which inhibits PDE9, a cGMP preferring phosphodiesterase.[34][35] PDE9 is expressed as high as PDE5 in the corpus cavernosum.[36]

PDE10 selective inhibitors

Papaverine, an opium alkaloid, has been reported to act as a PDE10 inhibitor.[37][38][39] 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".[40]

References

  1. ↑ "Multiple cyclic nucleotide phosphodiesterase activities from rat brain". Biochemistry 10 (2): 311–6. 1971. doi:10.1021/bi00778a018. PMID 4321663. 
  2. ↑ 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 (1): 220–226. doi:10.1016/0005-2744(72)90060-5. PMID 4342220. 
  3. ↑ Weiss B (1975). "Differential activation and inhibition of the multiple forms of cyclic nucleotide phosphodiesterase". Adv. Cycl. Nucl. Res. 5: 195–211. PMID 165666. 
  4. ↑ "Properties and drug responsiveness of cyclic nucleotide phosphodiesterases of rat lung". Mol. Pharmacol. 12 (4): 678–687. 1976. PMID 183099. 
  5. ↑ Weiss B.; Hait W.N. (1977). "Selective cyclic nucleotide phosphodiesterase inhibitors as potential therapeutic agents". Annu. Rev. Pharmacol. Toxicol. 17: 441–477. doi:10.1146/annurev.pa.17.040177.002301. PMID 17360. 
  6. ↑ 6.0 6.1 Essayan DM. (2001). "Cyclic nucleotide phosphodiesterases.". The Journal of Allergy and Clinical Immunology 108 (5): 671–80. doi:10.1067/mai.2001.119555. PMID 11692087. 
  7. ↑ 7.0 7.1 "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. 2008. doi:10.1590/S1807-59322008000300006. PMID 18568240. 
  8. ↑ "Pentoxifylline inhibits TNF-alpha production from human alveolar macrophages". Am. J. Respir. Crit. Care Med. 159 (2): 508–11. February 1999. doi:10.1164/ajrccm.159.2.9804085. PMID 9927365. 
  9. ↑ 9.0 9.1 "Leukotrienes: underappreciated mediators of innate immune responses". Journal of Immunology 174 (2): 589–94. 2005. doi:10.4049/jimmunol.174.2.589. PMID 15634873. 
  10. ↑ "Adenosine receptors: development of selective agonists and antagonists". Prog Clin Biol Res 230 (1): 41–63. 1987. PMID 3588607. 
  11. ↑ MacCorquodale, DW (July 1929). "The Synthesis of Some Alkylxanthines1,2". Journal of the American Chemical Society 51 (7): 2245–2251. doi:10.1021/ja01382a042. 
  12. ↑ 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.
  13. ↑ Constantin Koulbanis, Claude Bouillon, Patrick Darmenton,"Cosmetic compositions having a slimming action", US patent 4288433, granted 1981-09-04 , assigned to L'Oreal 
  14. ↑ "Analogues of caffeine and theophylline: effect of structural alterations on affinity at adenosine receptors". Journal of Medicinal Chemistry 29 (7): 1305–8. July 1986. doi:10.1021/jm00157a035. PMID 3806581. 
  15. ↑ "Adenosine receptors: development of selective agonists and antagonists". Progress in Clinical and Biological Research 230: 41–63. 1987. PMID 3588607. 
  16. ↑ "Caffeine and theophylline analogues: correlation of behavioral effects with activity as adenosine receptor antagonists and as phosphodiesterase inhibitors". Life Sciences 43 (5): 387–98. 1988. doi:10.1016/0024-3205(88)90517-6. PMID 2456442. https://zenodo.org/record/1253962. 
  17. ↑ "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. June 1989. doi:10.1021/jm00126a014. PMID 2724296. 
  18. ↑ "Caffeine analogs: structure-activity relationships at adenosine receptors". Pharmacology 42 (6): 309–21. 1991. doi:10.1159/000138813. PMID 1658821. https://zenodo.org/record/1235428. 
  19. ↑ "Adenosine receptor-blocking xanthines as inhibitors of phosphodiesterase isozymes". Biochemical Pharmacology 45 (4): 847–51. February 1993. doi:10.1016/0006-2952(93)90168-V. PMID 7680859. 
  20. ↑ Daly JW (July 2000). "Alkylxanthines as research tools". Journal of the Autonomic Nervous System 81 (1–3): 44–52. doi:10.1016/S0165-1838(00)00110-7. PMID 10869699. https://zenodo.org/record/1259863. 
  21. ↑ Daly JW (August 2007). "Caffeine analogs: biomedical impact". Cellular and Molecular Life Sciences 64 (16): 2153–69. doi:10.1007/s00018-007-7051-9. PMID 17514358. https://zenodo.org/record/1232583. 
  22. ↑ "Search for new antagonist ligands for adenosine receptors from QSAR point of view. How close are we?". Medicinal Research Reviews 28 (3): 329–71. May 2008. doi:10.1002/med.20108. PMID 17668454. 
  23. ↑ "Adenosine receptor antagonists: translating medicinal chemistry and pharmacology into clinical utility". Chemical Reviews 108 (1): 238–63. January 2008. doi:10.1021/cr0682195. PMID 18181659. 
  24. ↑ "Development of acute myocardial infarction in a young female patient with essential thrombocythemia treated with anagrelide: a case report". Korean J Hematol 45 (2): 136–8. 2010. doi:10.5045/kjh.2010.45.2.136. PMID 21120194. 
  25. ↑ "Phosphodiesterase-4 inhibition attenuates pulmonary inflammation in neonatal lung injury". Eur Respir J 31 (3): 633–644. 2008. doi:10.1183/09031936.00071307. PMID 18094015. 
  26. ↑ "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. 2009. doi:10.1016/j.ejphar.2009.10.031. PMID 19853596. 
  27. ↑ "Powered by Skipta technology, PharmacistSociety.com is the social network for verified Pharmacists to communicate and collaborate.". http://pharmacistsociety.skipta.com/article.aspx/o/4c18ca7f-1da9-4587-b304-64014e651663/09b6025d-60a0-4657-8b3f-b78ffc8f6f1c. 
  28. ↑ "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. 1988. doi:10.1007/BF00381071. PMID 3063534. 
  29. ↑ "Phosphodiesterase inhibitors: a novel mechanism for receptor-independent antipsychotic medications". Neuroscience 129 (1): 101–7. 2004. doi:10.1016/j.neuroscience.2004.07.038. PMID 15489033. 
  30. ↑ "Rolipram: A specific phosphodiesterase 4 inhibitor with potential antipsychotic activity". Neuroscience 144 (1): 239–46. 2006. doi:10.1016/j.neuroscience.2006.09.026. PMID 17081698. 
  31. ↑ "Sleep deprivation impairs cAMP signaling in the hippocampus". Nature 461 (7267): 1122–1125. 2009. doi:10.1038/nature08488. PMID 19847264. Bibcode: 2009Natur.461.1122V. 
  32. ↑ 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. doi:10.1016/j.ejmech.2011.10.040. PMID 22100138. 
  33. ↑ Guerreiro, Serge; Toulorge, Damien; Hirsch, Etienne; Marien, Marc; Sokoloff, Pierre; Michel, Patrick P. (October 2008). "Paraxanthine, the primary metabolite of caffeine, provides protection against dopaminergic cell death via stimulation of ryanodine receptor channels". Molecular Pharmacology 74 (4): 980–989. doi:10.1124/mol.108.048207. ISSN 1521-0111. PMID 18621927. 
  34. ↑ "Paraxanthine". https://www.caymanchem.com/pdfs/21068.pdf. 
  35. ↑ Orrú, Marco; Guitart, Xavier; Karcz-Kubicha, Marzena; Solinas, Marcello; Justinova, Zuzana; Barodia, Sandeep Kumar; Zanoveli, Janaina; Cortes, Antoni et al. (April 2013). "Psychostimulant pharmacological profile of paraxanthine, the main metabolite of caffeine in humans". Neuropharmacology 67C: 476–484. doi:10.1016/j.neuropharm.2012.11.029. ISSN 0028-3908. PMID 23261866. 
  36. ↑ da Silva, F H; Pereira, M N; Franco-Penteado, C F; De Nucci, G; Antunes, E; Claudino, M A (March 2013). "Phosphodiesterase-9 (PDE9) inhibition with BAY 73-6691 increases corpus cavernosum relaxations mediated by nitric oxide–cyclic GMP pathway in mice". International Journal of Impotence Research 25 (2): 69–73. doi:10.1038/ijir.2012.35. ISSN 0955-9930. PMID 23034509. 
  37. ↑ "Evaluating the antipsychotic profile of the preferential PDE10A inhibitor, papaverine". Psychopharmacology 203 (4): 723–35. May 2009. doi:10.1007/s00213-008-1419-x. PMID 19066855. 
  38. ↑ 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[yes|permanent dead link|dead link}}]
  39. ↑ Pöch, G.; Kukovetz, W.R. (1971). "Papaverine - induced inhibition of phosphodiesterase activity in various mammalian tissues". Life Sciences 10 (3): 133–144. doi:10.1016/0024-3205(71)90086-5. PMID 4325052. 
  40. ↑ 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; "Archived copy". http://www.ane.pl/pdf/7002.pdf. 



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