Description
Pergolide mesylate is a potent, long-acting dopamine agonist useful in the treatment of
Parkinson’s disease and hyperprolactinemia, Compared with lergotrile, pergolide mesylate
has shown less toxicity and lower propensity for inducing psychosis.
Description
Pergolide is a potent dopamine D
1 and D
2 receptor agonist (K
is = 111 and 0.495 nM, respectively, for rat striatal receptors). It depresses dopaminergic firing in paralyzed rats (ED
50 = <20 μg/kg), an effect that can be reversed by the dopamine D
2-selective antagonist spiperone or the dopamine D
1-selective antagonist SCH 23390 . Pergolide (0.025 and 0.05 mg/kg) increases the volume threshold for inducing bladder contraction in a cynomolgus monkey model of Parkinson''s disease induced by MPTP. It also reduces carrageenan-induced paw edema in adrenalectomized rats (ED
50 = 0.4 mg/kg).
Chemical Properties
White to Off-White Solid
Uses
dopamine receptor agonist, anti-Parkinson's agent
Uses
glucocorticoid, antiinflammatory
Uses
A dopaminergic agonist that also decrease plasma prolactin concentrations. An antiparkinsonian agent
Definition
ChEBI: A methanesulfonate salt obtained from pergolide by mixing eqimolar amount of pergolide and methanesulfonic acid. A dopamine D2 receptor agonist which also has D1 and D2 agonist properties, it i
used in the management of Parkinson's disease, although it was withdrawn from the U.S. and Canadian markets in 2007 due to an increased risk of cardiac valve dysfunction.
Manufacturing Process
Dimethyl disulfide (73.6 ml, 0.79 mol) and tri-n-butylphosphine (79.6 ml, 0.32 mol) were added to a solution of 9,10-dihydrolysergol in (8.1 g, 0.032 mol) in the 150 ml of anhydrous DMF and were stirred at room temperature for 6 hours under a nitrogen atmosphere. Dimethyl disulfide of the reaction mixture was removed under vacuo. A solution of the residue in ethyl acetate was extracted with 3.7% HCl (aq.). The aqueous layer was basified with ammonium hydroxide to a pH of 10 and then extracted with ethyl acetate. Removal of ethyl acetate followed by a silica gel column purification eluting with 10% MeOH/CH2Cl2 gave5.5.g of D-6-methyl-8β(methylthiomethyl)ergoline (60%).
A solution of D-6-methyl-8β-(methylthiomethyl)ergoline (0.4 g, 0.0014 mol) and NaI (0.63 g, 0.0042 mol) in 10 ml of propionic anhydride was refluxed for 40 hours. The reaction mixture was guenched with a 10% Na2CO3 solution and extracted by ethyl acetate. The combined organic layers were washed with a saturated brine solution, dried with magnesium sulfate and concentrated to produce oil. The oil was purified by silica gel column, eluting with 10% MeOH/CH2Cl2 to give 0.33 g of D-1,6-dipropionyl-8β(methylthiomethyl)ergoline.
LiAlH4 (0.6 g, 0.0156 mol) was slowly added to a solution of D-1,6dipropionyl-8β-(methylthiomethyl)ergoline in the 20 ml anhydrous THF at 0°C under nitrogene atmosphere. The mixture was stirred at 0°C for 30 min and then at room temperature for 4 hours. The reaction was cooled to 0°C and 0.6 ml of water was slowly added. The mixture was stirred at 0°C for 10 min and 1.8 ml of 15% NaOH (aq.) and 2.5 ml of water were added respectively. The mixture was stirred for 30 min at room temperature and then filtered. Excess of the solvent was removed under reduced pressure to give 150 mg of 8β-((methylthio)methyl)-6-propyl-ergoline or pergolide (yield: 68%). Ergoline,8-((methylthio)methyl)-6-propyl-, monomethanesulfonate, (8β)- may be prepared by mixing of components in solution.
brand name
Permax (Valeant).
Therapeutic Function
Dopamine agonist
Biochem/physiol Actions
Dopaminergic agonist; suppresses pituitary secretion of prolactin; anti-Parkinsonian agent.
References
[1] M MIYAGI. Dopamine receptor affinities in vitro and stereotypic activities in vivo of cabergoline in rats.[J]. Biological & pharmaceutical bulletin, 1996, 19 9: 1210-1213. DOI:
10.1248/bpb.19.1210[2] X X ZHANG Y F W G Z Jin. Agonistic actions of pergolide on firing activity of dopamine neurons in substantia nigra compacta area.[J]. Zhongguo yao li xue bao = Acta pharmacologica Sinica, 1995, 16 5: 423-427.
[3] N YOSHIMURA. Therapeutic effects of dopamine D1/D2 receptor agonists on detrusor hyperreflexia in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-lesioned parkinsonian cynomolgus monkeys.[J]. Journal of Pharmacology and Experimental Therapeutics, 1998, 286 1: 228-233.
[4] A M BENDELE. Anti-inflammatory activity of pergolide, a dopamine receptor agonist.[J]. Journal of Pharmacology and Experimental Therapeutics, 1991, 259 1: 169-175.
