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Identification
Name Rasagiline
Accession Number DB01367 (EXPT02758)
Type small molecule
Groups approved
Description

Rasagiline is an irreversible inhibitor of monoamine oxidase and is used as a monotherapy in early Parkinson’s disease or as an adjunct therapy in more advanced cases.
Structure Thumb
Download: MOL | SDF | SMILES | InChI
Display: 2D Structure | 3D Structure
Synonyms
RAS
Salts Not Available
Brand names
Name Company
Azilect
Brand mixtures Not Available
Categories
  • Neuroprotective Agents
  • Monoamine Oxidase Inhibitors
CAS number 136236-51-6
Weight Average: 171.2383
Monoisotopic: 171.104799421
Chemical Formula C12H13N
InChI Key InChIKey=RUOKEQAAGRXIBM-GFCCVEGCSA-N
InChI
InChI=1S/C12H13N/c1-2-9-13-12-8-7-10-5-3-4-6-11(10)12/h1,3-6,12-13H,7-9H2/t12-/m1/s1
Plain Text
IUPAC Name
(1R)-N-(prop-2-yn-1-yl)-2,3-dihydro-1H-inden-1-amine
SMILES
C#CCN[C@@H]1CCC2=CC=CC=C12
Plain Text
Mass Spec Not Available
Taxonomy
Kingdom Organic
Classes
  • Indanes
  • Phenylpropylamines
Substructures
  • Indanes
  • Alkynes
  • Aliphatic and Aryl Amines
  • Benzene and Derivatives
  • Aromatic compounds
  • Phenylpropylamines
Pharmacology
Indication For the treatment of the signs and symptoms of idiopathic Parkinsons disease as initial monotherapy and as adjunct therapy to levodopa.
Pharmacodynamics Rasagiline is a propargylamine and an irreversible inhibitor of monoamine oxidase (MAO). MAO, a flavin-containing enzyme, regulates the metabolic degradation of catecholamines and serotonin in the CNS and peripheral tissues. It is classified into two major molecular species, A and B, and is localized in mitochondrial membranes throughout the body in nerve terminals, brain, liver and intestinal mucosa. MAO-A is found predominantly in the GI tract and liver, and regulates the metabolic degradation of circulating catecholamines and dietary amines. MAO-B is the major form in the human brain and is responsible for the regulation of the metabolic degradation of dopamine and phenylethylamine. In ex vivo animal studies in brain, liver and intestinal tissues rasagiline was shown to be a potent,selective, and irreversible monoamine oxidase type B (MAO-B) inhibitor. At the recommended therapeutic doses, Rasagiline was also shown to be a potent and irreversible inhibitor of MAO-B in platelets. The selectivity of rasagiline for inhibiting only MAO-B (and not MAO-A) in humans and the sensitivity to tyramine during rasagiline treatment at any dose has not been sufficiently characterized to avoid restriction of dietary tyramine and amines contained in medications.
Mechanism of action The precise mechanisms of action of rasagiline is unknown. One mechanism is believed to be related to its MAO-B inhibitory activity, which causes an increase in extracellular levels of dopamine in the striatum. The elevated dopamine level and subsequent increased dopaminergic activity are likely to mediate rasagiline's beneficial effects seen in models of dopaminergic motor dysfunction.
Absorption Rasagiline is rapidly absorbed following oral administration. The absolute bioavailability of rasagiline is about 36%.
Volume of distribution
  • 87 L
Protein binding Plasma protein binding ranges from 88-94% with mean extent of binding of 61-63% to human albumin over the concentration range of 1-100 ng/ml.
Metabolism Rasagiline undergoes almost complete biotransformation in the liver prior to excretion. In vitro experiments indicate that both routes of rasagiline metabolism are dependent on the cytochrome P450 (CYP) system, with CYP 1A2 being the major isoenzyme involved in rasagiline metabolism.
Route of elimination Rasagiline undergoes almost complete biotransformation in the liver prior to excretion. Glucuronide conjugation of rasagiline and its metabolites, with subsequent urinary excretion, is the major elimination pathway. After oral administration of 14C-labeled rasagiline, elimination occurred primarily via urine and secondarily via feces (62% of total dose in urine and 7% of total dose in feces over 7 days), with a total calculated recovery of 84% of the dose over a period of 38 days. Less than 1% of rasagiline was excreted as unchanged drug in urine.
Half life Rasagiline has a mean steady-state half life of 3 hours but there is no correlation of pharmacokinetics with its pharmacological effect because of its irreversible inhibition of MAO-B.
Clearance Not Available
Toxicity Signs and symptoms of overdosage may include, alone or in combination, any of the following: drowsiness, dizziness, faintness, irritability, hyperactivity, agitation, severe headache, hallucinations, trismus, opisthotonos, convulsions, and coma; rapid and irregular pulse, hypertension, hypotension and vascular collapse; precordial pain, respiratory depression and failure, hyperpyrexia, diaphoresis, and cool, clammy skin.
Affected organisms
  • Humans and other mammals
Pathways Not Available
Pharmacoeconomics
Manufacturers
  • Teva neuroscience inc
Packagers
Dosage forms
Form Route Strength
Tablet Oral
Tablet Oral 0.5 mg
Tablet Oral 1 mg
Prices
Unit description Cost Unit
Azilect 0.5 mg tablet 12.11 USD tablet
Azilect 1 mg tablet 12.11 USD tablet
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
Patents
Country Patent Number Approved Expires (estimated)
United States 7572834 2006-12-05 2026-12-05
United States 5387612 1995-02-07 2012-02-07
Canada 2232310 2008-01-08 2016-09-18
Canada 2031714 1998-08-25 2010-12-06
Properties
State solid
Experimental Properties Not Available
Predicted Properties
Property Value Source
water solubility 2.49e-02 g/l ALOGPS
logP 2.26 ALOGPS
logP 2.3 ChemAxon
logS -3.8 ALOGPS
pKa (strongest basic) 8.69 ChemAxon
physiological charge 1 ChemAxon
hydrogen acceptor count 1 ChemAxon
hydrogen donor count 1 ChemAxon
polar surface area 12.03 ChemAxon
rotatable bond count 2 ChemAxon
refractivity 54.47 ChemAxon
polarizability 20.25 ChemAxon
References
Synthesis Reference Not Available
General Reference
  1. Weinreb O, Amit T, Bar-Am O, Youdim MB: RASAGILINE; A NOVEL ANTI-PARKINSONIAN MONOAMINE OXIDASE-B INHIBITOR WITH NEUROPROTECTIVE ACTIVITY. Prog Neurobiol. 2010 Jun 19. Pubmed
  2. Leegwater-Kim J, Bortan E: The role of rasagiline in the treatment of Parkinson’s disease. Clin Interv Aging. 2010 May 25;5:149-56. Pubmed
  3. Chen JJ, Swope DM, Dashtipour K: Comprehensive review of rasagiline, a second-generation monoamine oxidase inhibitor, for the treatment of Parkinson’s disease. Clin Ther. 2007 Sep;29(9):1825-49. Pubmed
External Links
Resource Link
KEGG Drug D02562 Link_out
PubChem Compound 3052776 Link_out
PubChem Substance 46506045 Link_out
ChemSpider 2314553 Link_out
BindingDB 10989 Link_out
Therapeutic Targets Database DAP001107 Link_out
PharmGKB PA164764584 Link_out
HET RAS Link_out
Drug Product Database 2284642 Link_out
RxList http://www.rxlist.com/cgi/generic/azilect.htm Link_out
Drugs.com http://www.drugs.com/cdi/rasagiline.html Link_out
Wikipedia http://en.wikipedia.org/wiki/Rasagiline Link_out
ATC Codes
  • N04BD02
AHFS Codes
  • 28:92.00
PDB Entries
FDA label show (200 KB)
MSDS Not Available
Interactions
Drug Interactions
Drug Interaction
Altretamine Risk of severe hypotension
Amitriptyline Possibility of severe adverse effects
Amoxapine Possibility of severe adverse effects
Amphetamine Possible hypertensive crisis
Atomoxetine Possible severe adverse reaction with this combination
Benzphetamine MAO Inhibitors may enhance the hypertensive effect of Amphetamines. Concomitant use of amphetamines and monoamine oxidase inhibitors (MAOI) should be avoided. If used concomitantly, careful monitoring of blood pressure must occur. It may take up to 2 weeks after the discontinuation of an MAOI for the effects to dissipate enough to afford safety to the administration of interacting agents.
Bezafibrate MAO Inhibitors may enhance the adverse/toxic effect of Bezafibrate. Avoid concomitant use of bezafibrate with monoamine oxidase inhibitors (MAOIs) rasagiline.
Brimonidine MAO Inhibitors like rasagiline may enhance the hypertensive effect of Alpha2-Agonists (Ophthalmic). The concomitant use of monoamine oxidase inhibitors and ophthalmic alpha2 agonists is contraindicated.
Buprenorphine Buprenorphine may enhance the adverse/toxic effect of MAO Inhibitors like rasagiline. When possible, avoid use of buprenorphine in patients who have used a monoamine oxidase inhibitor within the past 14 days due to possible severe adverse effects.
Bupropion Possible severe adverse reaction with this combination
Buspirone Possible blood pressure elevation
Ciprofloxacin Ciprofloxacin, a strong CYP1A2 inhibitor, may decrease the metabolism of rasagiline. Monitor for changes in the therapeutic and adverse effects of rasagiline if ciprofloxacin is initiated or discontinued.
Citalopram Possible severe adverse reaction with this combination
Clomipramine Possibility of severe adverse effects
Cyclobenzaprine Increased risk of toxicity with this association
Desipramine Possibility of severe adverse effects
Desvenlafaxine Increased risk of serotonin syndrome. Ensure adequate washout period between therapies to avoid toxicity. Concurrent therapy should be avoided.
Dexfenfluramine Possible hypertensive crisis
Dextroamphetamine Possible hypertensive crisis
Dextromethorphan Possible severe adverse reaction
Diethylpropion Possible hypertensive crisis
Dobutamine Increased arterial pressure
Dopamine Increased arterial pressure
Doxepin Possibility of severe adverse effects
Duloxetine Possible severe adverse reaction with this combination
Ephedra Increased arterial pressure
Ephedrine Increased arterial pressure
Epinephrine Increased arterial pressure
Escitalopram Possible severe adverse reaction with this combination
Fenfluramine Possible hypertensive crisis
Fenoterol Increased arterial pressure
Fluoxetine Possible severe adverse reaction with this combination
Fluvoxamine Possible severe adverse reaction with this combination
Imipramine Possibility of severe adverse effects
Isoproterenol Increased arterial pressure
Mazindol Possible hypertensive crisis
Meperidine Increased risk of serotonin syndrome. Concomitant use should be avoided.
Mephentermine Increased arterial pressure
Metaraminol Increased arterial pressure
Methamphetamine Possible hypertensive crisis
Methoxamine Increased arterial pressure
Methylphenidate Possible hypertensive crisis with this combination.
Midodrine Risk of hypertensive crisis.
Milnacipran Increase serotonin levels. Combination therapy is contraindicated.
Mirtazapine Possible severe adverse reaction with this combination
Nefazodone Possible severe adverse reaction with this combination
Norepinephrine Increased arterial pressure
Nortriptyline Possibility of severe adverse effects
Orciprenaline Increased arterial pressure
Paroxetine Possible severe adverse reaction with this combination
Phendimetrazine Possible hypertensive crisis
Phenmetrazine Possible hypertensive crisis
Phentermine Possible hypertensive crisis
Phenylephrine Increased arterial pressure
Phenylpropanolamine Increased arterial pressure
Pirbuterol Increased arterial pressure
Procaterol Increased arterial pressure
Protriptyline Possibility of severe adverse effects
Pseudoephedrine Increased arterial pressure
Salbutamol Increased arterial pressure
Sertraline Possible severe adverse reaction with this combination
Sibutramine Possible serotoninergic syndrome with this combination
St. John's Wort Increased risk of toxicity with this association
Tapentadol Increases the toxicity of tapentadol by unknown mechanism. Discontinue rasagiline at least 14 days prior to tapentadol administration.
Terbutaline Increased arterial pressure
Tetrabenazine Tetrabenazine may increase the adverse/toxic effects of Rasagiline. Concomitant therapy is contraindicated.
Tolcapone Tolcapone and Rasagiline decrease the metabolism of endogenous catecholamines. Concomitant therapy may result in increased catecholamine effects. Consider alternate therapy or use cautiously and monitor for increased catecholamine effects.
Tramadol Tramadol may increase the risk of serotonin syndrome and seizure induction by the MAO inhibitor, rasagiline.
Tranylcypromine Increased risk of serotonin syndrome. Use caution during concomitant therapy and monitor for symptoms of serotonin syndrome.
Trazodone Increased risk of serotonin syndrome. Monitor for symptoms of serotonin syndrome.
Trimipramine Increased risk of serotonin syndrome. Ensure adequate washout period between therapies to avoid toxicity. Avoid combination or monitor for symptoms of serotonin syndrome and/or hypertensive crisis.
Venlafaxine Increased risk of serotonin syndrome. Ensure adequate washout period between therapies to avoid toxicity. Concurrent therapy should be avoided.
Zolmitriptan The MAO inhibitor, rasagiline, may increase the serum concentration of zolmitriptan by decreasing its metabolism. Concomitant therapy and use of zolmitriptan within two weeks of discontinuing rasagiline are contraindicated.
Food Interactions
  • Avoid alcohol and caffeine.
Targets

1. Amine oxidase [flavin-containing] B

Pharmacological action: yes
Actions: inhibitor

Catalyzes the oxidative deamination of biogenic and xenobiotic amines and has important functions in the metabolism of neuroactive and vasoactive amines in the central nervous system and peripheral tissues. MAOB preferentially degrades benzylamine and phenylethylamine

Organism class: human
UniProt ID: P27338 Link_out
Gene: MAOB Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Naoi M, Maruyama W: Functional mechanism of neuroprotection by inhibitors of type B monoamine oxidase in Parkinson’s disease. Expert Rev Neurother. 2009 Aug;9(8):1233-50. Pubmed
  2. Uzun M, Alp R, Uzlu E, Alp S, Citil M, Topcu B, Erdogan HM: Investigation of oral selegiline and rasagiline administration on QT interval in conscious rabbits. Eur Rev Med Pharmacol Sci. 2009 Mar-Apr;13(2):95-8. Pubmed
  3. Youdim MB, Weinstock M: Molecular basis of neuroprotective activities of rasagiline and the anti-Alzheimer drug TV3326 [(N-propargyl-(3R)aminoindan-5-YL)-ethyl methyl carbamate]. Cell Mol Neurobiol. 2001 Dec;21(6):555-73. Pubmed
  4. Chau KY, Cooper JM, Schapira AH: Rasagiline protects against alpha-synuclein induced sensitivity to oxidative stress in dopaminergic cells. Neurochem Int. 2010 Jul 17. Pubmed
  5. Weinreb O, Amit T, Bar-Am O, Youdim MB: RASAGILINE; A NOVEL ANTI-PARKINSONIAN MONOAMINE OXIDASE-B INHIBITOR WITH NEUROPROTECTIVE ACTIVITY. Prog Neurobiol. 2010 Jun 19. Pubmed
  6. Youdim MB, Bar Am O, Yogev-Falach M, Weinreb O, Maruyama W, Naoi M, Amit T: Rasagiline: neurodegeneration, neuroprotection, and mitochondrial permeability transition. J Neurosci Res. 2005 Jan 1-15;79(1-2):172-9. Pubmed
  7. Leegwater-Kim J, Bortan E: The role of rasagiline in the treatment of Parkinson’s disease. Clin Interv Aging. 2010 May 25;5:149-56. Pubmed
  8. Chen JJ, Swope DM, Dashtipour K: Comprehensive review of rasagiline, a second-generation monoamine oxidase inhibitor, for the treatment of Parkinson’s disease. Clin Ther. 2007 Sep;29(9):1825-49. Pubmed
  9. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. Pubmed

2. Apoptosis regulator Bcl-2

Pharmacological action: yes
Actions: activator

Suppresses apoptosis in a variety of cell systems including factor-dependent lymphohematopoietic and neural cells. Regulates cell death by controlling the mitochondrial membrane permeability. Appears to function in a feedback loop system with caspases. Inhibits caspase activity either by preventing the release of cytochrome c from the mitochondria and/or by binding to the apoptosis-activating factor (APAF-1)

Organism class: human
UniProt ID: P10415 Link_out
Gene: BCL2 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Youdim MB, Weinstock M: Molecular basis of neuroprotective activities of rasagiline and the anti-Alzheimer drug TV3326 [(N-propargyl-(3R)aminoindan-5-YL)-ethyl methyl carbamate]. Cell Mol Neurobiol. 2001 Dec;21(6):555-73. Pubmed
  2. Akao Y, Maruyama W, Yi H, Shamoto-Nagai M, Youdim MB, Naoi M: An anti-Parkinson’s disease drug, N-propargyl-1®-aminoindan (rasagiline), enhances expression of anti-apoptotic bcl-2 in human dopaminergic SH-SY5Y cells. Neurosci Lett. 2002 Jun 28;326(2):105-8. Pubmed
  3. Maruyama W, Akao Y, Carrillo MC, Kitani K, Youdium MB, Naoi M: Neuroprotection by propargylamines in Parkinson’s disease: suppression of apoptosis and induction of prosurvival genes. Neurotoxicol Teratol. 2002 Sep-Oct;24(5):675-82. Pubmed
  4. Youdim MB, Amit T, Falach-Yogev M, Am OB, Maruyama W, Naoi M: The essentiality of Bcl-2, PKC and proteasome-ubiquitin complex activations in the neuroprotective-antiapoptotic action of the anti-Parkinson drug, rasagiline. Biochem Pharmacol. 2003 Oct 15;66(8):1635-41. Pubmed
  5. Bar-Am O, Weinreb O, Amit T, Youdim MB: Regulation of Bcl-2 family proteins, neurotrophic factors, and APP processing in the neurorescue activity of propargylamine. FASEB J. 2005 Nov;19(13):1899-901. Epub 2005 Sep 7. Pubmed
Enzymes

1. Cytochrome P450 1A2

Actions: substrate

Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally unrelated compounds, including steroids, fatty acids, and xenobiotics. Most active in catalyzing 2-hydroxylation. Caffeine is metabolized primarily by cytochrome CYP1A2 in the liver through an initial N3-demethylation. Also acts in the metabolism of aflatoxin B1 and acetaminophen

UniProt ID: P05177 Link_out
Gene: CYP1A2
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Lecht S, Haroutiunian S, Hoffman A, Lazarovici P: Rasagiline – a novel MAO B inhibitor in Parkinson’s disease therapy. Ther Clin Risk Manag. 2007 Jun;3(3):467-74. Pubmed
  2. Leegwater-Kim J, Bortan E: The role of rasagiline in the treatment of Parkinson’s disease. Clin Interv Aging. 2010 May 25;5:149-56. Pubmed
  3. Chen JJ, Swope DM, Dashtipour K: Comprehensive review of rasagiline, a second-generation monoamine oxidase inhibitor, for the treatment of Parkinson’s disease. Clin Ther. 2007 Sep;29(9):1825-49. Pubmed
  4. Preissner S, Kroll K, Dunkel M, Senger C, Goldsobel G, Kuzman D, Guenther S, Winnenburg R, Schroeder M, Preissner R: SuperCYP: a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions. Nucleic Acids Res. 2010 Jan;38(Database issue):D237-43. Epub 2009 Nov 24. Pubmed
Comments
Drug created on June 13, 2005 07:24 / Updated on February 08, 2013 16:20