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Chemical Compound Review

Deprenil     N-methyl-N-(1-phenylpropan-2- yl)prop-2-yn...

Synonyms: CHEBI:50217, CHEBI:118032, AR-1L0637, LS-103418, LS-171873, ...
 
 
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Disease relevance of selegiline

  • Disease progression, as monitored by five different assessment scales, was slowed (by 40 to 83% per year) in the deprenyl group compared to placebo [1].
  • Possible mechanism of action of deprenyl in parkinsonism [2].
  • Levodopa-treated Parkinson's disease patients who had been treated with deprenyl for up to 7 years, compared with patients who were changed to a placebo after about 5 years, experienced slower motor decline and were more likely to develop dyskinesias but less likely to develop freezing of gait [3].
  • Application of an antioxidant (gluthathione monoethyl ester), monoamine oxidase inhibitors (deprenyl, clogyline, paragyline), or an inhibitor of dopamine uptake (nomifensine) attenuated dopamine toxicity and dopamine-induced proteasome impairment [4].
  • Therefore, in the treatment of neurodegenerative diseases, reconsideration of the dosing schedule, by lowering the dose of deprenyl and choosing the most appropriate route of administration, would diminish undesired adverse effects, with unaltered neuroprotective potency [5].
 

Psychiatry related information on selegiline

 

High impact information on selegiline

 

Chemical compound and disease context of selegiline

 

Biological context of selegiline

  • In accordance with their potencies as enzyme inhibitors, binding to MAO-A and MAO-B was competitively inhibited by clorgyline (IC50 = 1.4 nM) and L-deprenyl (selegiline; IC50 = 8.0 nM), respectively [21].
  • Marked effect of liver and kidney function on the pharmacokinetics of selegiline [22].
  • Ischemia-induced delayed neuronal death can be mediated by apoptosis, and (-)deprenyl has been shown to block apoptosis in dopaminergic and cholinergic neurons [23].
  • However, even in the early clinical stage of PD, the sequence of events leading to nigral cell death may be too far advanced for selegiline to exhibit its maximum potential [24].
  • In addition, in the tilting test, the fall in diastolic blood pressure immediately after tilting and in systolic blood pressure 2 minutes after standing up was more pronounced in the selegiline group than in the placebo group [25].
 

Anatomical context of selegiline

 

Associations of selegiline with other chemical compounds

 

Gene context of selegiline

  • Possible mechanisms for the release-enhancing effect of the MAO-B inhibitors include elevation in levels of endogenous beta-phenylethylamine, or an inhibition of DA reuptake, which develops only on chronic administration, because both deprenyl and TVP-1012 have only very weak effects on amine uptake in acute experiments [33].
  • Deprenyl enantiomers and S-methamphetamine were substrates of human recombinant FMO3 [34].
  • The selectivity of the separate assays is further enhanced by the use of inhibitors, deprenyl to block MAO-B and clorgyline to block MAO-A [35].
  • In vitro, CYP2B6 was the most active form of p450 involved in selegiline metabolism [36].
  • Homology modeling suggested the participation of CYP2B6 in the demethylation of selegiline and of CYP2D6 in the depropargylation of the drug [36].
 

Analytical, diagnostic and therapeutic context of selegiline

References

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  2. Possible mechanism of action of deprenyl in parkinsonism. Paterson, I.A., Juorio, A.V., Boulton, A.A. Lancet (1990) [Pubmed]
  3. Impact of sustained deprenyl (selegiline) in levodopa-treated Parkinson's disease: a randomized placebo-controlled extension of the deprenyl and tocopherol antioxidative therapy of parkinsonism trial. Shoulson, I., Oakes, D., Fahn, S., Lang, A., Langston, J.W., LeWitt, P., Olanow, C.W., Penney, J.B., Tanner, C., Kieburtz, K., Rudolph, A. Ann. Neurol. (2002) [Pubmed]
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  5. Pharmacological aspects of (-)-deprenyl. Magyar, K., Pálfi, M., Tábi, T., Kalász, H., Szende, B., Szöko, E. Current medicinal chemistry. (2004) [Pubmed]
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  12. Monoamine oxidase: an important intracellular regulator of gastrin release in the rat. Dial, E.J., Huang, J., Delansorne, R., Lichtenberger, L.M. Gastroenterology (1986) [Pubmed]
  13. Oxidative stress and antioxidant therapy in Parkinson's disease. Ebadi, M., Srinivasan, S.K., Baxi, M.D. Prog. Neurobiol. (1996) [Pubmed]
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  15. Selegiline and lymphocyte superoxide dismutase activities in Parkinson's disease. Kushleika, J., Checkoway, H., Woods, J.S., Moon, J.D., Smith-Weller, T., Franklin, G.M., Swanson, P.D. Ann. Neurol. (1996) [Pubmed]
  16. MPTP, selegiline, and parkinsonism. Akos, K. Lancet (1987) [Pubmed]
  17. Serotonin syndrome and the combined use of deprenyl and an antidepressant in Parkinson's disease. Parkinson Study Group. Richard, I.H., Kurlan, R., Tanner, C., Factor, S., Hubble, J., Suchowersky, O., Waters, C. Neurology (1997) [Pubmed]
  18. The preventative role of antioxidants (selegiline and vitamin E) in a rat model of tardive dyskinesia. Sachdev, P., Saharov, T., Cathcart, S. Biol. Psychiatry (1999) [Pubmed]
  19. Carbidopa/levodopa and selegiline do not affect platelet mitochondrial function in early parkinsonism. Shults, C.W., Nasirian, F., Ward, D.M., Nakano, K., Pay, M., Hill, L.R., Haas, R.H. Neurology (1995) [Pubmed]
  20. Comparative effects of melatonin, L-deprenyl, Trolox and ascorbate in the suppression of hydroxyl radical formation during dopamine autoxidation in vitro. Khaldy, H., Escames, G., León, J., Vives, F., Luna, J.D., Acuña-Castroviejo, D. J. Pineal Res. (2000) [Pubmed]
  21. Quantitative enzyme radioautography with 3H-Ro 41-1049 and 3H-Ro 19-6327 in vitro: localization and abundance of MAO-A and MAO-B in rat CNS, peripheral organs, and human brain. Saura, J., Kettler, R., Da Prada, M., Richards, J.G. J. Neurosci. (1992) [Pubmed]
  22. Marked effect of liver and kidney function on the pharmacokinetics of selegiline. Anttila, M., Sotaniemi, E.A., Pelkonen, O., Rautio, A. Clin. Pharmacol. Ther. (2005) [Pubmed]
  23. (-)Deprenyl reduces delayed neuronal death of hippocampal pyramidal cells. Paterson, I.A., Barber, A.J., Gelowitz, D.L., Voll, C. Neuroscience and biobehavioral reviews. (1997) [Pubmed]
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  25. Selegiline diminishes cardiovascular autonomic responses in Parkinson's disease. Turkka, J., Suominen, K., Tolonen, U., Sotaniemi, K., Myllylä, V.V. Neurology (1997) [Pubmed]
  26. Pharmacokinetic aspects of l-deprenyl (selegiline) and its metabolites. Heinonen, E.H., Anttila, M.I., Lammintausta, R.A. Clin. Pharmacol. Ther. (1994) [Pubmed]
  27. Selegiline (deprenyl) treatment and death of nigral neurons in Parkinson's disease. Rinne, J.O., Röyttä, M., Paljärvi, L., Rummukainen, J., Rinne, U.K. Neurology (1991) [Pubmed]
  28. Chronic inhibition of the high-affinity dopamine uptake system increases oxidative damage to proteins in the aged rat substantia nigra. Romero-Ramos, M., Rodríguez-Gómez, J.A., Venero, J.L., Cano, J., Machado, A. Free Radic. Biol. Med. (1997) [Pubmed]
  29. Role of the redox protein thioredoxin in cytoprotective mechanism evoked by (-)-deprenyl. Andoh, T., Chock, P.B., Murphy, D.L., Chiueh, C.C. Mol. Pharmacol. (2005) [Pubmed]
  30. CYP2D6 polymorphism is not crucial for the disposition of selegiline. Scheinin, H., Anttila, M., Dahl, M.L., Karnani, H., Nyman, L., Taavitsainen, P., Pelkonen, O., Bertilsson, L. Clin. Pharmacol. Ther. (1998) [Pubmed]
  31. Analysis of deprenyl metabolites in the rat brain using HPLC-ES-MS. Kalász, H., Bartók, T., Szöko, E., Haberle, D., Kiss, J.P., Hennings, E.C., Magyar, K., Fürst, S. Current medicinal chemistry. (1999) [Pubmed]
  32. Tyramine kinetics and pressor sensitivity during monoamine oxidase inhibition by selegiline. Schulz, R., Antonin, K.H., Hoffmann, E., Jedrychowski, M., Nilsson, E., Schick, C., Bieck, P.R. Clin. Pharmacol. Ther. (1989) [Pubmed]
  33. Effect of long-term treatment with selective monoamine oxidase A and B inhibitors on dopamine release from rat striatum in vivo. Lamensdorf, I., Youdim, M.B., Finberg, J.P. J. Neurochem. (1996) [Pubmed]
  34. Assessment of the N-oxidation of deprenyl, methamphetamine, and amphetamine enantiomers by chiral capillary electrophoresis: an in vitro metabolism study. Szöko, E., Tábi, T., Borbás, T., Dalmadi, B., Tihanyi, K., Magyar, K. Electrophoresis (2004) [Pubmed]
  35. Rapid and simultaneous determination of monoamine oxidase A and monoamine oxidase B activities in mouse brain homogenates by liquid chromatography with electrochemical detection. Freeman, K.B., Bulawa, M.C., Zeng, Q., Blank, C.L. Anal. Biochem. (1993) [Pubmed]
  36. Comparative studies on the cytochrome p450-associated metabolism and interaction potential of selegiline between human liver-derived in vitro systems. Salonen, J.S., Nyman, L., Boobis, A.R., Edwards, R.J., Watts, P., Lake, B.G., Price, R.J., Renwick, A.B., Gómez-Lechón, M.J., Castell, J.V., Ingelman-Sundberg, M., Hidestrand, M., Guillouzo, A., Corcos, L., Goldfarb, P.S., Lewis, D.F., Taavitsainen, P., Pelkonen, O. Drug Metab. Dispos. (2003) [Pubmed]
  37. Intravenous self-administration studies with l-deprenyl (selegiline) in monkeys. Winger, G.D., Yasar, S., Negus, S.S., Goldberg, S.R. Clin. Pharmacol. Ther. (1994) [Pubmed]
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