desmethylselegiline

{{Drugbox

| Verifiedfields =

| Watchedfields =

| verifiedrevid =

| IUPAC_name = 1-Phenyl-N-prop-2-ynylpropan-2-amine

| image = Desmethylselegiline.svg

| width = 225px

| image2 = N-DesmethylselegilineMV.png

| tradename =

| pregnancy_AU =

| pregnancy_US =

| pregnancy_category =

| legal_AU =

| legal_CA =

| legal_UK =

| legal_US =

| legal_status =

| routes_of_administration = By mouth

| class = Monoamine oxidase inhibitor; Catecholaminergic activity enhancer; Norepinephrine–dopamine releasing agent

| bioavailability =

| protein_bound =

| metabolism =

| metabolites = •{{nbsp}}Levoamphetamine

| elimination_half-life =

| excretion =

| CAS_number_Ref =

| CAS_number = 18913-84-3

| CAS_supplemental =
2588-96-7 (HCl)

| ATC_prefix =

| ATC_suffix =

| ATC_supplemental =

| PubChem = 200718

| IUPHAR_ligand =

| DrugBank_Ref =

| DrugBank =

| ChemSpiderID_Ref =

| ChemSpiderID = 161558

| UNII =

| KEGG =

| ChEBI =

| ChEMBL = 1276

| synonyms = DMS; N-Desmethylselegiline; Norselegiline; L-Desmethyldeprenyl; L-DD; R-(–)-N-Desmethyldeprenyl; L-Nordeprenyl; N-Propargyl-L-amphetamine

| C = 12

| H = 15

| N = 1

| SMILES = CC(CC1=CC=CC=C1)NCC#C

| StdInChI_Ref =

| StdInChI = 1S/C12H15N/c1-3-9-13-11(2)10-12-7-5-4-6-8-12/h1,4-8,11,13H,9-10H2,2H3

| StdInChIKey_Ref =

| StdInChIKey = UUFAJPMQSFXDFR-UHFFFAOYSA-N

}}

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.{{cite journal | vauthors = Tábi T, Vécsei L, Youdim MB, Riederer P, Szökő É | title = Selegiline: a molecule with innovative potential | journal = Journal of Neural Transmission | volume = 127 | issue = 5 | pages = 831–842 | date = May 2020 | pmid = 31562557 | pmc = 7242272 | doi = 10.1007/s00702-019-02082-0 }}{{cite journal | vauthors = Mahmood I | title = Clinical pharmacokinetics and pharmacodynamics of selegiline. An update | journal = Clinical Pharmacokinetics | volume = 33 | issue = 2 | pages = 91–102 | date = August 1997 | pmid = 9260033 | doi = 10.2165/00003088-199733020-00002 }}{{cite journal | vauthors = Heinonen EH, Anttila MI, Lammintausta RA | title = Pharmacokinetic aspects of l-deprenyl (selegiline) and its metabolites | journal = Clinical Pharmacology and Therapeutics | volume = 56 | issue = 6 Pt 2 | pages = 742–749 | date = December 1994 | pmid = 7995016 | doi = 10.1038/clpt.1994.204 }}{{cite journal | vauthors = Heinonen EH, Anttila MI, Karnani HL, Nyman LM, Vuorinen JA, Pyykkö KA, Lammintausta RA | title = Desmethylselegiline, a metabolite of selegiline, is an irreversible inhibitor of monoamine oxidase type B in humans | journal = Journal of Clinical Pharmacology | volume = 37 | issue = 7 | pages = 602–609 | date = July 1997 | pmid = 9243353 | doi = 10.1002/j.1552-4604.1997.tb04342.x }}

Like selegiline, DMS is a monoamine oxidase inhibitor (MAOI); specifically, it is a selective and irreversible inhibitor of monoamine oxidase B (MAO-B). In addition, it is a catecholaminergic activity enhancer (CAE) similarly to selegiline.{{cite journal | vauthors = Miklya I | title = Essential difference between the pharmacological spectrum of (-)-deprenyl and rasagiline | journal = Pharmacological Reports | volume = 66 | issue = 3 | pages = 453–458 | date = June 2014 | pmid = 24905523 | doi = 10.1016/j.pharep.2013.11.003 }}{{cite journal | vauthors = Miklya I |title = (-)-deprenil, az N-metilprogargilamin-1-aminoindan (J-508) és a J-508 dezmetil analógjának (rasagilin) összehasonlító farmakológiai analízise | trans-title = A comparison of the pharmacology of (-)-deprenyl to N-methylpropargylamine-1-aminoindane (J-508) and rasagiline, the desmethyl-analogue of J-508 | language = Hungarian | journal = Neuropsychopharmacologia Hungarica | volume = 10 | issue = 1 | pages = 15–22 | date = March 2008 | pmid = 18771016 | url = https://mppt.hu/magazin/pdf/x-evfevfolyam-1-szam/a---deprenil-az-n.pdf }} The drug also produces levoamphetamine as an active metabolite, which is a norepinephrine–dopamine releasing agent with sympathomimetic and psychostimulant effects.

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

Pharmacology

= Pharmacodynamics =

DMS is a monoamine oxidase inhibitor (MAOI), similarly to selegiline. It is specifically a selective and irreversible inhibitor of monoamine oxidase B (MAO-B). The compound is also a catecholaminergic activity enhancer (CAE) like selegiline.{{cite journal | vauthors = Miklya I | title = Essential difference between the pharmacological spectrum of (-)-deprenyl and rasagiline | journal = Pharmacological Reports | volume = 66 | issue = 3 | pages = 453–458 | date = June 2014 | pmid = 24905523 | doi = 10.1016/j.pharep.2013.11.003 }}{{cite journal | vauthors = Miklya I |title = (-)-deprenil, az N-metilprogargilamin-1-aminoindan (J-508) és a J-508 dezmetil analógjának (rasagilin) összehasonlító farmakológiai analízise | trans-title = A comparison of the pharmacology of (-)-deprenyl to N-methylpropargylamine-1-aminoindane (J-508) and rasagiline, the desmethyl-analogue of J-508 | language = Hungarian | journal = Neuropsychopharmacologia Hungarica | volume = 10 | issue = 1 | pages = 15–22 | date = March 2008 | pmid = 18771016 | url = https://mppt.hu/magazin/pdf/x-evfevfolyam-1-szam/a---deprenil-az-n.pdf }} The potency of DMS as a CAE appears to be similar to that of selegiline.

Aside from being an active metabolite of selegiline, DMS itself has been studied clinically.{{cite journal | vauthors = Foley P, Gerlach M, Youdim MB, Riederer P | title = MAO-B inhibitors: multiple roles in the therapy of neurodegenerative disorders? | journal = Parkinsonism & Related Disorders | volume = 6 | issue = 1 | pages = 25–47 | date = January 2000 | pmid = 18591148 | doi = 10.1016/s1353-8020(99)00043-7 }} A single 10{{nbsp}}mg oral dose of DMS inhibited platelet MAO-B activity by 68 ± 16%, relative to 94 ± 9% with a single 10{{nbsp}}mg dose of selegiline. Subsequently, platelet MAO-B activity returned to baseline after 2{{nbsp}}weeks. Hence, although less potent than selegiline, DMS is also an effective MAO-B inhibitor.

DMS has been found to be 60-fold less potent than selegiline as an MAO-B inhibitor in vitro.{{cite book | vauthors = Borbe HO, Niebch G, Nickel B | chapter = Kinetic evaluation of MAO-B-activity following oral administration of selegiline and desmethyl-selegiline in the rat | title = Amine Oxidases and Their Impact on Neurobiology | series = Journal of Neural Transmission. Supplementum | volume = 32 | pages = 131–137 | date = 1990 | pmid = 2128496 | doi = 10.1007/978-3-7091-9113-2_18 | isbn = 978-3-211-82239-5 | chapter-url = }} However, it was only 3-fold less potent than selegiline orally in vivo in rats with repeated administration.{{cite journal | vauthors = Heinonen EH, Lammintausta R | title = A review of the pharmacology of selegiline | journal = Acta Neurologica Scandinavica. Supplementum | volume = 136 | issue = | pages = 44–59 | date = 1991 | pmid = 1686954 | doi = 10.1111/j.1600-0404.1991.tb05020.x }} In other research, DMS was 6-fold less potent than selegiline in inhibition of platelet MAO-B activity.{{cite thesis | vauthors = Heinonen EH | title = Selegiline in the treatment of Parkinson's disease: Pharmacokinetic and clinical studies | date = 1995 | publisher = University of Turku | location = Turku, Finland | url = https://scholar.google.com/scholar?cluster=12861509981083590652}}

Selegiline produces levomethamphetamine and levoamphetamine as active metabolites, whereas DMS produces only levoamphetamine as a metabolite. Unlike DMS and selegiline, levoamphetamine and levomethamphetamine are not active as MAO-B inhibitors at concentrations up to 100{{nbsp}}μM in vitro.{{cite journal | vauthors = Mahmood I, Neau SH, Mason WD | title = An enzymatic assay for the MAO-B inhibitor selegiline in plasma | journal = Journal of Pharmaceutical and Biomedical Analysis | volume = 12 | issue = 7 | pages = 895–899 | date = July 1994 | pmid = 7981318 | doi = 10.1016/0731-7085(93)e0021-e }} However, levoamphetamine is a releaser of norepinephrine and dopamine and has sympathomimetic and psychostimulant effects.{{cite journal | vauthors = Heal DJ, Smith SL, Gosden J, Nutt DJ | title = Amphetamine, past and present--a pharmacological and clinical perspective | journal = Journal of Psychopharmacology | volume = 27 | issue = 6 | pages = 479–496 | date = June 2013 | pmid = 23539642 | pmc = 3666194 | doi = 10.1177/0269881113482532 }}{{cite journal | vauthors = Smith RC, Davis JM | title = Comparative effects of d-amphetamine, l-amphetamine, and methylphenidate on mood in man | journal = Psychopharmacology | volume = 53 | issue = 1 | pages = 1–12 | date = June 1977 | pmid = 407607 | doi = 10.1007/BF00426687 }}{{#tag:ref|Smith & Davis (1977) reviewed 11{{nbsp}}clinical studies of dextroamphetamine and levoamphetamine including doses and potency ratios in terms of a variety of psychological and behavioral effects. The summaries of these studies are in Table 1 of the paper.|name=smith-davis-1977-review|group=note}} Similarly to selegiline, but unlike levoamphetamine and levomethamphetamine, DMS itself is not a monoamine releasing agent.{{cite journal | vauthors = Knoll J | title = (-)Deprenyl (selegiline), a catecholaminergic activity enhancer (CAE) substance acting in the brain | journal = Pharmacology & Toxicology | volume = 82 | issue = 2 | pages = 57–66 | date = February 1998 | pmid = 9498233 | doi = 10.1111/j.1600-0773.1998.tb01399.x }}

DMS shows neuroprotective, antioxidant, and antiapoptotic activity similarly to selegiline.{{cite journal | vauthors = Mytilineou C, Leonardi EK, Radcliffe P, Heinonen EH, Han SK, Werner P, Cohen G, Olanow CW | title = Deprenyl and desmethylselegiline protect mesencephalic neurons from toxicity induced by glutathione depletion | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 284 | issue = 2 | pages = 700–706 | date = February 1998 | pmid = 9454817 | doi = }}{{cite journal | vauthors = Mytilineou C, Radcliffe PM, Olanow CW | title = L-(-)-desmethylselegiline, a metabolite of selegiline [L-(-)-deprenyl], protects mesencephalic dopamine neurons from excitotoxicity in vitro | journal = Journal of Neurochemistry | volume = 68 | issue = 1 | pages = 434–436 | date = January 1997 | pmid = 8978757 | doi = 10.1046/j.1471-4159.1997.68010434.x }}{{cite journal | vauthors = Tatton WG, Chalmers-Redman RM | title = Modulation of gene expression rather than monoamine oxidase inhibition: (-)-deprenyl-related compounds in controlling neurodegeneration | journal = Neurology | volume = 47 | issue = 6 Suppl 3 | pages = S171–S183 | date = December 1996 | pmid = 8959986 | doi = 10.1212/wnl.47.6_suppl_3.171s }} DMS is more potent in some of these effects than selegiline. The neuroprotective and antioxidant properties of DMS and selegiline appear to be independent of MAO-B inhibition. 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.{{cite journal | vauthors = Gerlach M, Reichmann H, Riederer P | title=A critical review of evidence for preclinical differences between rasagiline and selegiline | journal=Basal Ganglia | volume=2 | issue=4 | date=2012 | doi=10.1016/j.baga.2012.04.032 | pages=S9–S15 }}{{cite journal | vauthors = Tatton W, Chalmers-Redman R, Tatton N | title = Neuroprotection by deprenyl and other propargylamines: glyceraldehyde-3-phosphate dehydrogenase rather than monoamine oxidase B | journal = Journal of Neural Transmission | volume = 110 | issue = 5 | pages = 509–515 | date = May 2003 | pmid = 12721812 | doi = 10.1007/s00702-002-0827-z }}

= Pharmacokinetics =

Selegiline and DMS were compared in a clinical study in which 10{{nbsp}}mg of each drug was administered orally. 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.

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

Selegiline is metabolized into DMS in the liver. 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.{{cite journal | vauthors = Gerlach M, Youdim MB, Riederer P | title = Pharmacology of selegiline | journal = Neurology | volume = 47 | issue = 6 Suppl 3 | pages = S137–S145 | date = December 1996 | pmid = 8959982 | doi = 10.1212/wnl.47.6_suppl_3.137s }} Levoamphetamine is formed with selegiline from both DMS and levomethamphetamine.{{cite journal | vauthors = Barkholtz HM, Hadzima R, Miles A | title = Pharmacology of R-(-)-Methamphetamine in Humans: A Systematic Review of the Literature | journal = ACS Pharmacology & Translational Science | volume = 6 | issue = 7 | pages = 914–924 | date = July 2023 | pmid = 37470013 | pmc = 10353062 | doi = 10.1021/acsptsci.3c00019 }} However, levoamphetamine is only a minor metabolite of levomethamphetamine (2–3%). As a metabolite of selegiline, DMS has an elimination half-life ranging from 2.6 to 11{{nbsp}}hours. The half-lives of both selegiline and DMS increase with continuous use of selegiline.

Chemistry

= Prodrugs =

Prodrugs of DMS have been synthesized and studied.{{cite journal | vauthors = Dalvie D, Kalgutkar AS | title=Utilizing mechanistic organic chemistry training to study drug metabolism in preclinical drug discovery/development | journal=Medicinal Chemistry Research | volume=32 | issue=9 | date=2023 | issn=1054-2523 | doi=10.1007/s00044-023-03085-z | pages=1922–1932}}{{cite journal | vauthors = Flaherty P, Castagnoli K, Wang YX, Castagnoli N | title = 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 = Journal of Medicinal Chemistry | volume = 39 | issue = 24 | pages = 4756–4761 | date = November 1996 | pmid = 8941389 | doi = 10.1021/jm960477e }}