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Desmethylselegiline

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Desmethylselegiline (DMS), also known as norselegiline or as N-propargyl-L-amphetamine, is an active metabolite of selegiline, a medication used in the treatment of Parkinson's disease and depression.[4][1][2][3]

Desmethylselegiline
Clinical data
Other namesDMS; N-Desmethylselegiline; Norselegiline; L-Desmethyldeprenyl; L-DD; R-(–)-N-Desmethyldeprenyl; L-Nordeprenyl; N-Propargyl-L-amphetamine
Routes of
administration		By mouth[1][2][3]
Drug classMonoamine oxidase inhibitor; Catecholaminergic activity enhancer; Norepinephrine–dopamine releasing agent
Pharmacokinetic data
Metabolites• Levoamphetamine[4][1][3]
Identifiers
  • 1-Phenyl-N-prop-2-ynylpropan-2-amine
CAS Number
PubChem CID
ChemSpider
ChEMBL
CompTox Dashboard (EPA)
Chemical and physical data
FormulaC12H15N
Molar mass173.259 g·mol−1
3D model (JSmol)
  • CC(CC1=CC=CC=C1)NCC#C
  • InChI=1S/C12H15N/c1-3-9-13-11(2)10-12-7-5-4-6-8-12/h1,4-8,11,13H,9-10H2,2H3
  • Key:UUFAJPMQSFXDFR-UHFFFAOYSA-N

Like selegiline, DMS is a monoamine oxidase inhibitor (MAOI); specifically, it is a selective and irreversible inhibitor of monoamine oxidase B (MAO-B).[1][2][3] In addition, it is a catecholaminergic activity enhancer (CAE) similarly to selegiline.[5][6] The drug also produces levoamphetamine as an active metabolite, which is a norepinephrine–dopamine releasing agent with sympathomimetic and psychostimulant effects.[1][7][8]

DMS has been studied much less extensively than selegiline and has not been developed or approved for medical use.[9]

Pharmacology

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Pharmacodynamics

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DMS is a monoamine oxidase inhibitor (MAOI), similarly to selegiline.[1][2][3] It is specifically a selective and irreversible inhibitor of monoamine oxidase B (MAO-B).[1][2][3] The compound is also a catecholaminergic activity enhancer (CAE) like selegiline.[5][6] The potency of DMS as a CAE appears to be similar to that of selegiline.[5][6]

Aside from being an active metabolite of selegiline, DMS itself has been studied clinically.[1][10][3] A single 10 mg oral dose of DMS inhibited platelet MAO-B activity by 68 ± 16%, relative to 94 ± 9% with a single 10 mg dose of selegiline.[1][2][3] Subsequently, platelet MAO-B activity returned to baseline after 2 weeks.[1][2][3] Hence, although less potent than selegiline, DMS is also an effective MAO-B inhibitor.[1][10][3]

DMS has been found to be 60-fold less potent than selegiline as an MAO-B inhibitor in vitro.[1][2][11] However, it was only 3-fold less potent than selegiline orally in vivo in rats with repeated administration.[1][2][9][11] In other research, DMS was 6-fold less potent than selegiline in inhibition of platelet MAO-B activity.[1][12]

Selegiline produces levomethamphetamine and levoamphetamine as active metabolites, whereas DMS produces only levoamphetamine as a metabolite.[1] Unlike DMS and selegiline, levoamphetamine and levomethamphetamine are not active as MAO-B inhibitors at concentrations up to 100 μM in vitro.[1][13] However, levoamphetamine is a releaser of norepinephrine and dopamine and has sympathomimetic and psychostimulant effects.[7][8][note 1] Similarly to selegiline, but unlike levoamphetamine and levomethamphetamine, DMS itself is not a monoamine releasing agent.[14]

DMS shows neuroprotective, antioxidant, and antiapoptotic activity similarly to selegiline.[10][15][16][17] DMS is more potent in some of these effects than selegiline.[10][16][17] The neuroprotective and antioxidant properties of DMS and selegiline appear to be independent of MAO-B inhibition.[10][15][16][17] Both selegiline and DMS have been found to bind to and inhibit glyceraldehyde-3-phosphate dehydrogenase (GAPDH), which may be involved in their neuroprotective effects.[18][19]

Pharmacokinetics

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Selegiline and DMS were compared in a clinical study in which 10 mg of each drug was administered orally.[3] DMS showed 27-fold higher peak levels and 33-fold higher area-under-the-curve levels than selegiline in this study, suggesting that it has much greater oral bioavailability than selegiline.[3]

Levoamphetamine is an active metabolite of DMS.[4][1][3] Conversely, in contrast to selegiline, which metabolizes into both levomethamphetamine and levoamphetamine, levomethamphetamine is not a metabolite of DMS.[4][1][3]

Selegiline is metabolized into DMS in the liver.[20] With use of oral selegiline in humans, 86% of a dose is excreted in urine, with 1.1% of this being DMS, 59.2% being levomethamphetamine, and 26.3% being levoamphetamine.[20] Levoamphetamine is formed with selegiline from both DMS and levomethamphetamine.[20][21] However, levoamphetamine is only a minor metabolite of levomethamphetamine (2–3%).[21] As a metabolite of selegiline, DMS has an elimination half-life ranging from 2.6 to 11 hours.[1] The half-lives of both selegiline and DMS increase with continuous use of selegiline.[1]

Chemistry

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Prodrugs

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Prodrugs of DMS have been synthesized and studied.[22][23]

Notes

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  1. ^ Smith & Davis (1977) reviewed 11 clinical studies of dextroamphetamine and levoamphetamine including doses and potency ratios in terms of a variety of psychological and behavioral effects.[8] The summaries of these studies are in Table 1 of the paper.[8]

References

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  1. ^ a b c d e f g h i j k l m n o p q r s t Mahmood I (August 1997). "Clinical pharmacokinetics and pharmacodynamics of selegiline. An update". Clinical Pharmacokinetics. 33 (2): 91–102. doi:10.2165/00003088-199733020-00002. PMID 9260033.
  2. ^ a b c d e f g h i Heinonen EH, Anttila MI, Lammintausta RA (December 1994). "Pharmacokinetic aspects of l-deprenyl (selegiline) and its metabolites". Clinical Pharmacology and Therapeutics. 56 (6 Pt 2): 742–749. doi:10.1038/clpt.1994.204. PMID 7995016.
  3. ^ a b c d e f g h i j k l m n Heinonen EH, Anttila MI, Karnani HL, Nyman LM, Vuorinen JA, Pyykkö KA, et al. (July 1997). "Desmethylselegiline, a metabolite of selegiline, is an irreversible inhibitor of monoamine oxidase type B in humans". Journal of Clinical Pharmacology. 37 (7): 602–609. doi:10.1002/j.1552-4604.1997.tb04342.x. PMID 9243353.
  4. ^ a b c d Tábi T, Vécsei L, Youdim MB, Riederer P, Szökő É (May 2020). "Selegiline: a molecule with innovative potential". Journal of Neural Transmission. 127 (5): 831–842. doi:10.1007/s00702-019-02082-0. PMC 7242272. PMID 31562557.
  5. ^ a b c Miklya I (June 2014). "Essential difference between the pharmacological spectrum of (-)-deprenyl and rasagiline". Pharmacological Reports. 66 (3): 453–458. doi:10.1016/j.pharep.2013.11.003. PMID 24905523.
  6. ^ a b c Miklya I (March 2008). "(-)-deprenil, az N-metilprogargilamin-1-aminoindan (J-508) és a J-508 dezmetil analógjának (rasagilin) összehasonlító farmakológiai analízise" [A comparison of the pharmacology of (-)-deprenyl to N-methylpropargylamine-1-aminoindane (J-508) and rasagiline, the desmethyl-analogue of J-508] (PDF). Neuropsychopharmacologia Hungarica (in Hungarian). 10 (1): 15–22. PMID 18771016.
  7. ^ a b Heal DJ, Smith SL, Gosden J, Nutt DJ (June 2013). "Amphetamine, past and present--a pharmacological and clinical perspective". Journal of Psychopharmacology. 27 (6): 479–496. doi:10.1177/0269881113482532. PMC 3666194. PMID 23539642.
  8. ^ a b c d Smith RC, Davis JM (June 1977). "Comparative effects of d-amphetamine, l-amphetamine, and methylphenidate on mood in man". Psychopharmacology. 53 (1): 1–12. doi:10.1007/BF00426687. PMID 407607.
  9. ^ a b Heinonen EH, Lammintausta R (1991). "A review of the pharmacology of selegiline". Acta Neurologica Scandinavica. Supplementum. 136: 44–59. doi:10.1111/j.1600-0404.1991.tb05020.x. PMID 1686954.
  10. ^ a b c d e Foley P, Gerlach M, Youdim MB, Riederer P (January 2000). "MAO-B inhibitors: multiple roles in the therapy of neurodegenerative disorders?". Parkinsonism & Related Disorders. 6 (1): 25–47. doi:10.1016/s1353-8020(99)00043-7. PMID 18591148.
  11. ^ a b Borbe HO, Niebch G, Nickel B (1990). "Kinetic evaluation of MAO-B-activity following oral administration of selegiline and desmethyl-selegiline in the rat". Amine Oxidases and Their Impact on Neurobiology. Journal of Neural Transmission. Supplementum. Vol. 32. pp. 131–137. doi:10.1007/978-3-7091-9113-2_18. ISBN 978-3-211-82239-5. PMID 2128496.
  12. ^ Heinonen EH (1995). Selegiline in the treatment of Parkinson's disease: Pharmacokinetic and clinical studies (Thesis). Turku, Finland: University of Turku.
  13. ^ Mahmood I, Neau SH, Mason WD (July 1994). "An enzymatic assay for the MAO-B inhibitor selegiline in plasma". Journal of Pharmaceutical and Biomedical Analysis. 12 (7): 895–899. doi:10.1016/0731-7085(93)e0021-e. PMID 7981318.
  14. ^ Knoll J (February 1998). "(-)Deprenyl (selegiline), a catecholaminergic activity enhancer (CAE) substance acting in the brain". Pharmacology & Toxicology. 82 (2): 57–66. doi:10.1111/j.1600-0773.1998.tb01399.x. PMID 9498233.
  15. ^ a b Mytilineou C, Leonardi EK, Radcliffe P, Heinonen EH, Han SK, Werner P, et al. (February 1998). "Deprenyl and desmethylselegiline protect mesencephalic neurons from toxicity induced by glutathione depletion". The Journal of Pharmacology and Experimental Therapeutics. 284 (2): 700–706. PMID 9454817.
  16. ^ a b c Mytilineou C, Radcliffe PM, Olanow CW (January 1997). "L-(-)-desmethylselegiline, a metabolite of selegiline [L-(-)-deprenyl], protects mesencephalic dopamine neurons from excitotoxicity in vitro". Journal of Neurochemistry. 68 (1): 434–436. doi:10.1046/j.1471-4159.1997.68010434.x. PMID 8978757.
  17. ^ a b c Tatton WG, Chalmers-Redman RM (December 1996). "Modulation of gene expression rather than monoamine oxidase inhibition: (-)-deprenyl-related compounds in controlling neurodegeneration". Neurology. 47 (6 Suppl 3): S171–S183. doi:10.1212/wnl.47.6_suppl_3.171s. PMID 8959986.
  18. ^ Gerlach M, Reichmann H, Riederer P (2012). "A critical review of evidence for preclinical differences between rasagiline and selegiline". Basal Ganglia. 2 (4): S9–S15. doi:10.1016/j.baga.2012.04.032.
  19. ^ Tatton W, Chalmers-Redman R, Tatton N (May 2003). "Neuroprotection by deprenyl and other propargylamines: glyceraldehyde-3-phosphate dehydrogenase rather than monoamine oxidase B". Journal of Neural Transmission. 110 (5): 509–515. doi:10.1007/s00702-002-0827-z. PMID 12721812.
  20. ^ a b c Gerlach M, Youdim MB, Riederer P (December 1996). "Pharmacology of selegiline". Neurology. 47 (6 Suppl 3): S137–S145. doi:10.1212/wnl.47.6_suppl_3.137s. PMID 8959982.
  21. ^ a b Barkholtz HM, Hadzima R, Miles A (July 2023). "Pharmacology of R-(-)-Methamphetamine in Humans: A Systematic Review of the Literature". ACS Pharmacology & Translational Science. 6 (7): 914–924. doi:10.1021/acsptsci.3c00019. PMC 10353062. PMID 37470013.
  22. ^ Dalvie D, Kalgutkar AS (2023). "Utilizing mechanistic organic chemistry training to study drug metabolism in preclinical drug discovery/development". Medicinal Chemistry Research. 32 (9): 1922–1932. doi:10.1007/s00044-023-03085-z. ISSN 1054-2523.
  23. ^ Flaherty P, Castagnoli K, Wang YX, Castagnoli N (November 1996). "Synthesis and selective monoamine oxidase B-inhibiting properties of 1-methyl-1,2,3,6-tetrahydropyrid-4-yl carbamate derivatives: potential prodrugs of (R)- and (S)-nordeprenyl". Journal of Medicinal Chemistry. 39 (24): 4756–4761. doi:10.1021/jm960477e. PMID 8941389.
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