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Chemical compound From Wikipedia, the free encyclopedia
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]
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| Other names | DMS; 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] |
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| Chemical and physical data | |
| Formula | C12H15N |
| Molar mass | 173.259 g·mol−1 |
| 3D model (JSmol) | |
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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]
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]
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]
Prodrugs of DMS have been synthesized and studied.[22][23]
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