Desmethylselegiline

Last updated

Desmethylselegiline
Desmethylselegiline.svg
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 class Monoamine 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
Formula C12H15N
Molar mass 173.259 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

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]

Contents

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

Pharmacodynamics

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

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

Prodrugs

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

Notes

  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]

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References

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