(2R,4R,7R)-4-[(methylsulfanyl)methyl]-6-propyl-6,11-diazatetracyclo[7.6.1.0^{2,7}.0^{12,16}]hexadeca-1(16),9,12,14-tetraene

• ChemBase ID: 1057
• Molecular Formular: C19H26N2S
• Molecular Mass: 314.48814
• Monoisotopic Mass: 314.18166984
• SMILES: S(C[C@@H]1C[C@H]2[C@H](N(C1)CCC)Cc1c3c2cccc3[nH]c1)C
• Canonical SMILES: CCCN1C[C@H](CSC)C[C@H]2[C@H]1Cc1c[nH]c3c1c2ccc3
• InChI: InChI=1S/C19H26N2S/c1-3-7-21-11-13(12-22-2)8-16-15-5-4-6-17-19(15)14(10-20-17)9-18(16)21/h4-6,10,13,16,18,20H,3,7-9,11-12H2,1-2H3/t13-,16-,18-/m1/s1
• InChIKey: YEHCICAEULNIGD-MZMPZRCHSA-N

NAMES AND DATABASE IDS

Names

• IUPAC name: (2R,4R,7R)-4-[(methylsulfanyl)methyl]-6-propyl-6,11-diazatetracyclo[7.6.1.0^{2,7}.0^{12,16}]hexadeca-1(16),9,12,14-tetraene; (2R,4R,7R)-4-[(methylsulfanyl)methyl]-6-propyl-6,11-diazatetracyclo[7.6.1.0^2,^7.0^1^2,^1^6]hexadeca-1(16),9,12,14-tetraene
• IUPAC Traditional name: pergolide
• Brand Name: Permax
• Synonyms: Pergolida [INN-Spanish]; Pergolide Mesylate; Pergolide Methanesulfonate; Pergolidum [INN-Latin]; Pergolide; (8β)-8-[(Methylthio)methyl]-6-propylergoline Mesylate; Celance; Permax; Nopar; LY-127809; Pergolide Mesylate

Database IDs

• CAS Number: 66104-22-1; 66104-23-2
• PubChem SID: 46507604; 160964520
• PubChem CID: 47811

CALCULATED PROPERTIES

JChem

• Acid pKa: 17.350344
• H Acceptors: 1
• H Donor: 1
• LogD (pH = 5.5): 0.84682393
• LogD (pH = 7.4): 2.1517017
• Log P: 4.22529
• Molar Refractivity: 97.0167 cm^3
• Polarizability: 38.847607 Å^3
• Polar Surface Area: 19.03 Å^2
• Rotatable Bonds: 4
• Lipinski's Rule of Five: true

ALOGPS 2.1

• Log P: 4.17
• LOG S: -5.73
• Solubility (Water): 5.84e-04 g/l

PROPERTIES

Physical Property

• Solubility: DMSO; Methanol (Sparingly)
• Apperance: White to Off-White Solid
• Melting Point: >232°C (dec.)
• Hydrophobicity(logP): 4

Safety Information

• Storage Condition: -20°C Freezer

DETAILS

DrugBank - DB01186

• Drug Groups: approved; withdrawn
• Description: Pergolide is a long-acting dopamine agonist approved in 1982 for the treatment of Parkinson’s Disease. It is an ergot derivative that acts on the dopamine D2 and D3, alpha2- and alpha1-adrenergic, and 5-hydroxytryptamine (5-HT) receptors. It was indicated as adjunct therapy with levodopa/carbidopa in the symptomatic treatment of parkinsonian syndrome. It was later found that pergolide increased the risk of cardiac valvulopathy. The drug was withdrawn from the US market in March 2007 and from the Canadian market in August 2007.
• Indication: Indicated as adjunctive treatment to levodopa/carbidopa in the management of the signs and symptoms of Parkinson's disease. It was withdrawn from the US and Canadian markets in 2007 due to an increased risk of cardiac valvulopathy.
• Pharmacology: Pergolide stimulates centrally-located dopaminergic receptors resulting in a number of pharmacologic effects. Five dopamine receptor types from two dopaminergic subfamilies have been identified. The dopaminergic D1 receptor subfamily consists of D₁ and D₅ subreceptors and are associated with dyskinesias. The dopaminergic D2 receptor subfamily consists of D₂, D₃ and D₄ subreceptors and has been associated with improvement of symptoms of movement disorders. Thus, agonist activity specific for D2 subfamily receptors, primarily D₂ and D₃ receptor subtypes, are the primary targets of dopaminergic antiparkinsonian agents. It is thought that postsynaptic D2 stimulation is primarily responsible for the antiparkinsonian effect of dopamine agonists, while presynaptic D2 stimulation confers neuroprotective effects. This semisynthetic ergot derivative exhibits potent agonist activity on dopamine D₂- and D₃-receptors. It also exhibits agonist activity on dopamine D₄, D₁, and D₅, 5-hydroxytryptamine (5-HT)_1A, 5-HT_1B, 5-HT_1D, 5-HT_2A, 5-HT_2B, 5-HT_2C, α_2A-, α_2B-, α_2C-, α_1A-, α_1B-, and α_1D-adrenergic receptors. Parkinsonian Syndrome manifests when approximately 80% of dopaminergic activity in the nigrostriatal pathway of the brain is lost. As this striatum is involved in modulating the intensity of coordinated muscle activity (e.g. movement, balance, walking), loss of activity may result in dystonia (acute muscle contraction), Parkinsonism (including symptoms of bradykinesia, tremor, rigidity, and flattened affect), akathesia (inner restlessness), tardive dyskinesia (involuntary muscle movements usually associated with long-term loss of dopaminergic activity), and neuroleptic malignant syndrome, which manifests when complete blockage of nigrostriatal dopamine occurs. High dopaminergic activity in the mesolimbic pathway of the brain causes hallucinations and delusions; these side effects of dopamine agonists are manifestations seen in patients with schizophrenia who have overractivity in this area of the brain. The hallucinogenic side effects of dopamine agonists may also be due to 5-HT_2A agonism. The tuberoinfundibular pathway of the brain originates in the hypothalamus and terminates in the pituitary gland. In this pathway, dopamine inhibits lactotrophs in anterior pituitary from secreting prolactin. Increased dopaminergic activity in the tuberoinfundibular pathway inhibits prolactin secretion. Pergolide also causes transient increases in somatotropin (growth hormone) secretion and decreases in luteinizing hormone (LH) concentrations.
• Toxicity: Oral, rat LD₅₀: 15 mg/kg. Symptoms of overdose include nausea, vomiting, convulsions, decreased blood pressure, and CNS stimulation.
• Affected Organisms: Humans and other mammals
• Biotransformation: Extensively hepatic.
• Absorption: Significant amount may be absorbed (evidence on bioavailability still lacking).
• Half Life: 27 hours
• Protein Binding: 90%
• Elimination: The major route of excretion is the kidney.
• References: Schade R, Andersohn F, Suissa S, Haverkamp W, Garbe E: Dopamine agonists and the risk of cardiac-valve regurgitation. N Engl J Med. 2007 Jan 4;356(1):29-38. [Pubmed] ; Breitenstein C, Korsukewitz C, Floel A, Kretzschmar T, Diederich K, Knecht S: Tonic dopaminergic stimulation impairs associative learning in healthy subjects. Neuropsychopharmacology. 2006 Nov;31(11):2552-64. Epub 2006 Jul 26. [Pubmed]
• External Links: Wikipedia; RxList; Drugs.com

Toronto Research Chemicals - P287200

A dopaminergic agonist that also decrease plasma prolactin concentrations. An antiparkinsonian agent.

REFERENCES

• Schade R, Andersohn F, Suissa S, Haverkamp W, Garbe E: Dopamine agonists and the risk of cardiac-valve regurgitation. N Engl J Med. 2007 Jan 4;356(1):29-38. Pubmed
• Breitenstein C, Korsukewitz C, Floel A, Kretzschmar T, Diederich K, Knecht S: Tonic dopaminergic stimulation impairs associative learning in healthy subjects. Neuropsychopharmacology. 2006 Nov;31(11):2552-64. Epub 2006 Jul 26. Pubmed
• Lemberger, L. and Crabtree, R.E.: Science, 205, 1151 (1979)
• Koller, W.C.: Neuropharmacology, 19, 831 (1979)
• Francks, S., et al.: Lancet, 2, 659 (1979)
• Kleinberg, D.L., et al.: N. Engl. J. Med., 309, 704 (1983)