In a concentration-dependent manner, selegiline hydrochloride (1 nM-1 μM) inhibits recombinant human MAO-B[1]. Selegiline (10 mM) hydrochloride enhanced norepinephrine (NE), dopamine (DA), and serotonin (5-HT) efflux from the rat hypothalamus in vitro tests. In a dose-dependent manner, selegiline hydrochloride inhibits the efflux of 5-hydroxyindoleacetic acid (5-HIAA) and dihydroxyphenylacetic acid (DOPAC) [3].

In mice, selegiline hydrochloride (1 mg/kg; intraperitoneal injection daily for 24 days) decreased cocaine self-administration but had no effect on weight loss caused by cocaine. The concentrations of 5-hydroxyindoleacetic acid (5-HIAA) and 3,4-dihydroxyphenylacetic acid (DOPAC) in the frontal cortex are lowered by selegiline hydrochloride [4].

Animal/Disease Models: Male C57BL/6J mice (20-22 g) [4]
Doses: 1 mg/kg
Route of Administration: daily intraperitoneal (ip) injection for 24 days
Experimental Results: A single injection does not seriously affect the locomotor activities of mice . Dosing for 14 days did not affect food reward. diminished cocaine self-administration and diminished DOPAC and 5-HIAA concentrations in the frontal cortex.

Absorption, Distribution and Excretion
Selegiline and its metabolites are widely distributed into body tissues and cross the blood-brain barrier. Following IV administration of radiolabeled selegiline hydrochloride in mice, the parent drug and/or metabolites are rapidly and widely distributed to brain, liver, kidney, lung, heart, and brown fat. Following IV administration of radiolabeled selegiline hydrochloride in healthy adults, the highest accumulation of radioactivity occurred in the thalamus, basal ganglia, mesencephalon, and cingulate gyrus. /Selegiline/
Selegiline is excreted principally in urine as conjugated and unconjugated metabolites. About 20-63% of an orally administered dose of selegiline is excreted in urine as l-methamphetamine, 9-26% as l-amphetamine, and 1% as l-demethylselegiline. ... About 15% of a dose is excreted in feces within 72 hours following administration of selegiline. /SRP: This would usually result in a false positive drug test for d-methamphetamine if no d/l-isomer characterization was performed on the specimen./ /Selegiline/
Rapidly absorbed from the gastrointestinal tract.
... The mean peak plasma concentration (Cmax) is approximately 2 ug/L and the time to reach the peak is under an hour. The absolute bioavailability of selegiline is approximately 10%. It has an apparent volume of distribution of 1854 L. The oral clearance of selegiline (59 L/min) is many fold higher than the liver blood flow (1.5 L/min), indicating that extrahepatic processes are involved in the elimination of selegiline. ... /Selegiline/
... Selegiline is readily absorbed from the gastrointestinal tract and rapidly enters the brain and spinal cord following oral administration. The drug binds to brain regions with a high MAO-B content, such as the thalamus, the striatum, the cortex, and the brainstem. ... /Selegiline/

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Metabolism / Metabolites
Selegiline is excreted principally in urine as conjugated and unconjugated metabolites. About 20-63% of an orally administered dose of selegiline is excreted in urine as l-methamphetamine, 9-26% as l-amphetamine, and 1% as l-demethylselegiline. /Selegiline/
Rapidly and completely metabolized to N-desmethyldeprenyl, l-methamphetamine, and l-amphetamine.
Selegiline is extensively metabolized, presumably through cytochrome p450 mediated oxygenation, to form l-desmethylselegiline and l-methamphetamine, which is further metabolized to l-amphetamine. Selegiline also is metabolized in the lungs to l-desmethylselegiline and l-methamphetamine and in the kidneys to l-methamphetamine, but the degree of metabolism in these tissues is minimal compared with that in the liver. /Selegiline/
... The pharmacokinetics of selegiline are highly variable. Following an oral dose of selegiline 10 mg, it is rapidly absorbed and metabolized to desmethylselegiline, levoamphetamine and levomethamphetamine. /Selegiline/
For more Metabolism/Metabolites (Complete) data for SELEGILINE HYDROCHLORIDE (6 total), please visit the HSDB record page.

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Biological Half-Life
Elimination: Selegiline: 39 (range, 16 to 69) hours. /Selegiline/
The mean half-lives of the 3 active metabolites that were found in serum and urine following a single dose of selegiline are as follows: N-desmethyldeprenyl, 2 hours; l-amphetamine, 17.7 hours; l-methamphetamine, 20.5 hours. /Selegiline/

Effects During Pregnancy and Lactation
◉ Summary of Use during Lactation
A minimal amount of clinical use of selegiline during breastfeeding has been reported. Although no adverse reactions have been reported in the breastfed infants, an alternate drug may be preferred, especially while nursing a newborn or preterm infant. The manufacturer of the selegiline transdermal patch recommends that breastfeeding is not recommended during treatment and for 7 days after the final dose.
◉ Effects in Breastfed Infants
A woman took selegiline 10 mg, levodopa 400 mg and benserazide 100 mg daily throughout pregnancy and continued them while breastfeeding her infant for 3 days. The child was followed for 10 years and no developmental abnormalities were found.
A woman with severe depression used a selegiline patch 6 mg per day during pregnancy and postpartum. She exclusively breastfed her infant for an unstated period of time. Pediatric follow-up at 5 months of age found that the infant was developing normally.
◉ Effects on Lactation and Breastmilk
Selegiline can decrease serum prolactin in women with migraine, and in those taking neuroleptic drugs. The clinical relevance of these findings in nursing mothers is not known. The prolactin level in a mother with established lactation may not affect her ability to breastfeed.

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Interactions
Although some patients appear to be sensitive to the hypertensive effects of sympathomimetic agents during therapy with a nonselective MAO inhibitor, nonprescription (over-the-counter, OTC) or prescription cold or hay fever preparations that contain pressor agents (e.g., ephedrine, phenylpropanolamine) generally can be given to patients receiving selegiline hydrochloride dosages of 10 mg or less daily without undue risk of uncontrolled hypertension. However, hypertensive crisis was reported in at least one patient receiving the recommended 10 mg daily dosage of selegiline hydrochloride and a sympathomimetic agent (ephedrine).
In patients receiving levodopa, addition of selegiline hydrochloride may exacerbate levodopa-associated dyskinesias. This effect, which occurred in an average of 28% (range: 4-90%) of patients receiving the drug in clinical trials, usually occurs within 2 weeks after initiating selegiline therapy and generally is mitigated when the levodopa dosage is reduced ... . Bruxism, muscle twitching and myoclonic jerks have occurred in patients receiving levodopa and selegiline hydrochloride dosages exceeding 10 mg daily.
Asystole, diaphoresis, hypertension, syncope, changes in behavior and mental status, impaired consciousness, hyperpyrexia, seizures, muscular rigidly, and tremors have occurred with concurrent use of selegiline and tricyclic antidepressants. Concurrent use is not recommended; at least 14 days should elapse between discontinuation of selegiline and initiation of a tricyclic antidepressant. /Selegiline/
A reaction resembling the serotonin syndrome has been reported rarely following concurrent use of selegiline with selective serotonin re-uptake inhibitors (SSRIs). (The serotonin syndrome may occur as the result of combining a serotonergic agent with an MAO inhibitor. The syndrome may be manifest by mental status changes (confusion, hypomania), restlessness, myoclonus, hyperreflexia, diaphoresis, shivering, tremor, diarrhea, incoordination, and/or fever. If recognized early, the syndrome usually resolves quickly upon withdrawal of the offending agents.) Concurrent use of selegiline with SSRIs is not recommended because of the potential for autonomic instability, muscular rigidity, severe agitation, or delirium. At least 14 days should elapse between discontinuation of an MAO inhibitor and initiation of an SSRI. However, because of the long half-lives of fluoxetine and its active metabolite, at least 5 weeks (approximately 5 half-lives) should elapse between discontinuation of fluoxetine and initiation of therapy with an MAO inhibitor. ALso, based on the half-life of venlafaxine, at least 7 days should elapse between discontinuation of venlafaxine and initiation of therapy with an MAO inhibitor. /Selegiline/
For more Interactions (Complete) data for SELEGILINE HYDROCHLORIDE (9 total), please visit the HSDB record page.

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Non-Human Toxicity Values
LD50 Rat sc 280 mg/kg
LD50 Rat iv 81 mg/kg

[1]. Selective Inhibition of Human Monoamine Oxidase B by Acacetin 7-Methyl Ether Isolated from Turnera diffusa (Damiana). Molecules. 2019 Feb 23;24(4):810.

[2]. Modulation of gene expression rather than monoamine oxidase inhibition: (-)-deprenyl-related compounds in controlling neurodegeneration. Neurology. 1996 Dec;47(6 Suppl 3):S171-83.

[3]. Deprenyl stimulates the efflux of monoamines from the rat hypothalamus in vitro. Brain Res Bull. 2001 Apr;54(6):675-80.

[4]. Chronic treatment with monoamine oxidase-B inhibitors decreases cocaine reward in mice. Psychopharmacology (Berl). 2009 Jul;205(1):141-9.

Selegiline Hydrochloride is the hydrochloride salt form of selegiline, a levorotatory acetylenic derivative of phenethylamine with antiparkinsonian effect. As a selective monoamine oxidase (MAO) inhibitor, selegiline has the greatest affinity for type B MAO, found mainly in the brain. Selegiline is converted by MAO B to an active moiety, which binds irreversibly at the active site of the enzyme's cofactor FAD (flavin adenine dinucleotide) molecule. This prevents the oxidative deamination of catecholamines and serotonin by MAO B, and leads to an increase in these neurotransmitters' activities resulting in improved motor function. In addition, this agent may inhibit re-uptake of dopamine by the neuron and prolong dopamine activity.
A selective, irreversible inhibitor of Type B monoamine oxidase that is used for the treatment of newly diagnosed patients with PARKINSON DISEASE, and for the treatment of depressive disorders. The compound without isomeric designation is Deprenyl.
See also: Selegiline (has active moiety).

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Mechanism of Action
The action of selegiline is thought to be related to its irreversible inhibition of monoamine oxidase type B (MAO B), the major form of the enzyme in the human brain. MAO B, which is involved in the oxidative deamination of dopamine in the brain, is inhibited when selegiline binds covalently and stoichiometrically to the isoalloxazine flavin adenine dinucleotide (FAD) at its active center. Administration of 10 mg of selegiline a day produces almost complete inhibition of MAO B in the brain. Selegiline becomes a nonselective inhibitor of all monamine oxidase (MAO) at higher doses, possibly at 20 to 40 mg a day. At these doses, tyramine-mediated hypertensive reaction with MAO A blockade ("cheese reactions") may occur. /Selegiline/
Selegiline (or its metabolites) may also act through other mechanisms to increase dopaminergic activity, including interfering with dopamine reuptake at the synapse. /Selegiline/
The mechanism of action of selegiline is complex and cannot be explained solely by its MAO-B inhibitory action. Pretreatment with selegiline can protect neurons against a variety of neurotoxins, such as 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine (MPTP), 6-hydroxydopamine, N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4), methyl-beta-acetoxyethyl-2-chloroethylamine (AF64A), and 5,6-dihydroxyserotonin, which damage dopaminergic, adrenergic, cholinergic, and sertoninergic neurons, respectively. Selegiline produces an amphetamine-like effect, enhances the release of dopamine, and blocks the reuptake of dopamine. It stimulates gene expression of L-aromatic amino acid decarboxylase, increases striatal phenylethylamine levels, and activates dopamine receptors. Selegiline reduces the production of oxidative radicals, up-regulates superoxide dismutase and catalase, and suppresses nonenzymatic and iron-catalyzed autooxidation of dopamine. Selegiline compensates for loss of target-derived trophic support, delays apoptosis in serum-deprived cells, and blocks apoptosis-related fall in the mitochondrial membrane potential. Most of the aforementioned properties occur independently of selegiline's efficacy to inhibit MAO-B. /Selegiline/
Selegiline is a selective inhibitor of monoamine oxidase-B (MAO-B) at a dose of 10 mg/day and is given to patients with Parkinson's disease as an adjunct to levodopa therapy. By inhibiting MAO-B, selegiline increases the dopamine levels in the substantia nigra. Selegiline also blocks dopamine re-uptake from the synaptic cleft, thus increasing the dopamine concentrations in the brain. ... /Selegiline/
For more Mechanism of Action (Complete) data for SELEGILINE HYDROCHLORIDE (6 total), please visit the HSDB record page.

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Therapeutic Uses
Monamine oxidase B inhibitor
Selegiline is indicated for use with levodopa or levodopa and carbidopa combination in the treatment of idiopathic Parkinson's disease (paralysis agitans). /Included in US product labeling/ /Selegiline/
.... we report briefly on neurotoxicity associated with the immunodeficiency virus and discuss the effects of selegiline, a monoamine oxidase inhibitor which enhances dopamine availability in CNS on immunodeficiency virus-induced neurological disease. ... /MAO inhibitors may be potent mediators of the neuropathological deficits in immunodeficiency virus infection and factors which may accelerate the progression of the immunodeficiency virus --neurological disease./
EXPTL Therapy: ... Twenty patients with mild-moderate pathological cerebral involution of atrophic and/or vascular origin, were treated with Selegiline (L-deprenyl), a monoamino-oxidase B inhibitor (10 mg/day for six months). Compared with a control group, Selegiline treated patients showed a statistically significant improvement in cognitive and behaviour capacities. At the end of investigation, "Mini Mental State" showed an improvement of 26.5% in Selegiline group and of 3.7% in control group (P < 0.01). "Echelle Clinique d'Aptitudes Intellectuelles" showed an improvement of 29.4% and of 10.8% respectively (P < 0.01). Selegiline treatment has shortened significantly the reaction times and has improved mnesic capacities. No side effects were observed during the study. /Selegiline/
For more Therapeutic Uses (Complete) data for SELEGILINE HYDROCHLORIDE (10 total), please visit the HSDB record page.

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Drug Warnings
Pregnancy risk category: C /RISK CANNOT BE RULED OUT. Adequate, well controlled human studies are lacking, and animal studies have shown risk to the fetus or are lacking as well. There is a chance of fetal harm if the drug is given during pregnancy; but the potential benefits may outweigh the potential risk./
Selegiline may decrease or inhibit salivary flow, thus contributing to the development of caries, periodontal disease, oral candidiasis, and discomfort.
Therapeutic use may lead to increased tremor, bradykinesia, falling, dystonic symptoms, dyskinesias, hallucinations, confusion, sleep disturbance, headache, dry mouth, blurred vision, orthostatic hypotension, hypertension, poor appetite, urinary retention, and diaphoresis. Hypomanic behavior may be due to the l-amphetamine and l-amphetamine metabolites of selegiline.
In patients receiving levodopa, addition of selegiline hydrochloride may exacerbate levodopa-associated dyskinesias. This effect, which occurred in an average of 28% (range: 4-90%) of patients receiving the drug in clinical trials, usually occurs within 2 weeks after initiating selegiline therapy and generally is mitigated when the levodopa dosage is reduced ... . Involuntary movements, increased tremor, chorea, loss of balance, freezing, blepharospasm, increased bradykinesia, facial grimacing, speech problems, heavy leg, stiff neck, tardive dyskinesia, dystonic manifestations, festination, increased apraxia, and muscle cramping may occur in patients receiving selegiline. Bruxism, muscle twitching and myoclonic jerks have occurred in patients receiving levodopa and selegiline hydrochloride dosages exceeding 10 mg daily.
For more Drug Warnings (Complete) data for SELEGILINE HYDROCHLORIDE (12 total), please visit the HSDB record page.

C13H17N.HCL

223.74172

223.112

14611-52-0

Selegiline;14611-51-9

26758

White to off-white solid powder

0.954g/cm3

272.5ºC at 760mmHg

141-142ºC

108.4ºC

2.984

1

1

4

15

195

1

C[C@H](CC1=CC=CC=C1)N(C)CC#C.Cl

IYETZZCWLLUHIJ-UTONKHPSSA-N

InChI=1S/C13H17N.ClH/c1-4-10-14(3)12(2)11-13-8-6-5-7-9-13;/h1,5-9,12H,10-11H2,2-3H3;1H/t12-;/m1./s1

(2R)-N-methyl-1-phenyl-N-prop-2-ynylpropan-2-amine;hydrochloride

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Note: Please store this product in a sealed and protected environment, avoid exposure to moisture.

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO : ~100 mg/mL (~446.95 mM)
H2O : ≥ 33.33 mg/mL (~148.97 mM)

Solubility in Formulation 1: ≥ 5 mg/mL (22.35 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 50.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 5 mg/mL (22.35 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 50.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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 (Please use freshly prepared in vivo formulations for optimal results.)