Pergolide

Pergolide, sold under the brand name Permax and Prascend (veterinary) among others, is an ergoline-based dopamine receptor agonist used in some countries for the treatment of Parkinson's disease. Parkinson's disease is associated with reduced dopamine activity in the substantia nigra of the brain. Pergolide acts on many of the same receptors as dopamine to increase receptor activity.

Pergolide
Clinical data
Trade namesPermax, Prascend (veterinary), others
Other names8β-[(Methylthio)methyl]-6-propylergoline
AHFS/Drugs.comMonograph
Pregnancy
category
  • B
Routes of
administration		Oral
ATC code
Legal status
Legal status
  • US: Veterinary use only, withdrawn for human use
Pharmacokinetic data
Protein binding90%
MetabolismExtensively Hepatic
Elimination half-life27 hours
Identifiers
IUPAC name
  • (6aR,9R,10aR)-9-(methylthiomethyl)-7-propyl-4,6,6a,7,8,9,10,10a-octahydroindolo[4,3-fg]quinoline
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard100.241.322
Chemical and physical data
FormulaC19H26N2S
Molar mass314.49 g·mol−1
3D model (JSmol)
SMILES
  • [H][C@]12C[C@@H](CSC)CN(CCC)[C@]1([H])Cc3c[nH]c4cccc2c34
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 Y
  • Key:YEHCICAEULNIGD-MZMPZRCHSA-N Y
 NY (what is this?)  (verify)

It was patented in 1978[1] and approved for medical use in 1989.[2] In 2007, pergolide was withdrawn from the U.S. market for human use after several published studies revealed a link between the drug and increased rates of valvular heart disease.[3] However, a veterinary form of pergolide, marketed under the trade name Prascend, is permitted for the treatment of pituitary pars intermedia dysfunction (PPID) also known as equine Cushing's syndrome (ECS) in horses.[4]

Medical uses

Pergolide is not available for use by humans in the United States, however, it is still used in various other countries, where it is used to treat various conditions including Parkinson's disease, hyperprolactinemia, and restless leg syndrome.

Pergolide is available for veterinary use. Under the trade name Prascend, manufactured by Boehringer Ingelheim,[5] it is commonly used for the treatment of pituitary hyperplasia at the pars intermedia or Equine Cushing's Syndrome (ECS) in horses.[6]

Pharmacology

Pharmacodynamics

Pergolide acts as an agonist of dopamine D2 and D1 and serotonin 5-HT1A, 5-HT1B, 5-HT2A, 5-HT2B, and 5-HT2C receptors. It may possess agonist activity at other dopamine receptor subtypes as well, similar to cabergoline. Although pergolide is more potent as an agonist of the D2 receptor, it has high D1 receptor affinity and is one of the most potent D1 receptor agonists of the dopamine receptor agonists that are clinically available.[7] The agonist activity of pergolide at the D1 receptor somewhat alters its clinical and side effect profile in the treatment of Parkinson's disease. Pergolide is said to be hallucinogenic due to activation of 5-HT2A receptors.[8][9] It has been associated with cardiac valvulopathy due to activation of 5-HT2B receptors.[10]

Activities of pergolide at various sites[11][12][13][14]
Site Affinity (Ki [nM]) Efficacy (Emax [%]) Action
D1 339  ?  ?
D2S 32 112 Full agonist
D2L 26 52 Partial agonist
D3 5.5 71 Partial agonist
D4 59 56 Partial agonist
D5 33  ?  ?
5-HT1A 1.9 63 Partial agonist
5-HT1B 282 90 Partial agonist
5-HT1D 13 86 Partial agonist
5-HT2A 8.3 103 Full agonist
5-HT2B 7.1 113 Full agonist
5-HT2C 295 87 Partial agonist
5-HT6 30  ?  ?
5-HT7 1.0–18  ?  ?
α1A 1,047  ?  ?
α1B 692  ?  ?
α1D 295  ?  ?
α2A 50 31 Partial agonist
α2B 32 70 Partial agonist
α2C 68 16 Partial agonist
α2D 692  ?  ?
β1 >10,000 – –
β2 >10,000 – –
H1 1,698  ?  ?
M1 >10,000 – –
σ1 >10,000 – –
σ2 923  ?  ?
Notes: All receptors are human except α2D-adrenergic, which is rat (no human counterpart), and 5-HT6, 5-HT7, σ1, and σ2, which are all rodent (rat or guinea pig).[11][14]

Side effects

The drug is in decreasing use, as it was reported in 2003 to be associated with a form of heart disease called cardiac fibrosis.[15] In 2007, The United States Food and Drug Administration announced a voluntary withdrawal of the drug by manufacturers due to the possibility of heart valve damage.[16] Pergolide is not currently available in the United States for human use. This problem is thought to be due to pergolide's action at the 5-HT2B serotonin receptors of cardiac myocytes, causing proliferative valve disease by the same mechanism as ergotamine, methysergide, fenfluramine, and other serotonin 5-HT2B agonists, including serotonin itself when elevated in the blood in carcinoid syndrome. Pergolide can rarely cause Raynaud's phenomenon. Among similar antiparkinsonian drugs, cabergoline but not lisuride exhibit this same type of serotonin receptor binding.[17] In January, 2007, cabergoline (Dostinex) was reported also to be associated with valvular proliferation heart damage.[18] In March 2007, pergolide was withdrawn from the U.S. market for human use, due to serious valvular damage that was shown in two independent studies.[19]

Pergolide has also been shown to impair associative learning.[20]

Addictive behaviors

At least one British pergolide user has attracted some media attention with claims that it has caused him to develop a gambling addiction.[21][22] In June 2010, it was reported that more than 100 Australian users of the drug are suing the manufacturer over both gambling and sex addiction[23] problems they claim are the result of the drug's side effects.

Society and culture

Brand names

Brand names of pergolide include Permax and Prascend (veterinary), among others.[24]

References
  1. US patent 4166182A, Edmund C. Kornfeld & Nicholas J. Bach, "6-n-propyl-8-methoxymethyl or methylmercaptomethylergolines and related compounds", published 1979-08-28, issued 1979-08-28, assigned to Eli Lilly and Co
  2. Fischer, Jnos; Ganellin, C. Robin (2006). Analogue-based Drug Discovery. John Wiley & Sons. p. 533. ISBN 9783527607495.
  3. FDA Public Health Advisory: Pergolide (marketed as Permax)
  4. "Pergolide for Veterinary Use".
  5. "Prascend for Horses Boehringer Ingelheim - Safe.Pharmacy|Metabolic | Horse Rx | Equine".
  6. Barbara Forney, VMD. "Pergolide For Veterinary Use".
  7. McClure, Margaret M; Harvey, Philip D; Goodman, Marianne; Triebwasser, Joseph; New, Antonia; Koenigsberg, Harold W; Sprung, Larry J; Flory, Janine D; Siever, Larry J (2010). "Pergolide Treatment of Cognitive Deficits Associated with Schizotypal Personality Disorder: Continued Evidence of the Importance of the Dopamine System in the Schizophrenia Spectrum". Neuropsychopharmacology. 35 (6): 1356–1362. doi:10.1038/npp.2010.5. ISSN 0893-133X. PMC 3055340. PMID 20130535.
  8. Gillman PK (February 2010). "Triptans, serotonin agonists, and serotonin syndrome (serotonin toxicity): a review". Headache. 50 (2): 264–72. doi:10.1111/j.1526-4610.2009.01575.x. PMID 19925619. S2CID 221752556.
  9. Cussac D, Boutet-Robinet E, Ailhaud MC, Newman-Tancredi A, Martel JC, Danty N, Rauly-Lestienne I (October 2008). "Agonist-directed trafficking of signalling at serotonin 5-HT2A, 5-HT2B and 5-HT2C-VSV receptors mediated Gq/11 activation and calcium mobilisation in CHO cells". Eur J Pharmacol. 594 (1–3): 32–8. doi:10.1016/j.ejphar.2008.07.040. PMID 18703043.
  10. Cavero I, Guillon JM (2014). "Safety Pharmacology assessment of drugs with biased 5-HT(2B) receptor agonism mediating cardiac valvulopathy". J Pharmacol Toxicol Methods. 69 (2): 150–61. doi:10.1016/j.vascn.2013.12.004. PMID 24361689.
  11. Millan MJ, Maiofiss L, Cussac D, Audinot V, Boutin JA, Newman-Tancredi A (November 2002). "Differential actions of antiparkinson agents at multiple classes of monoaminergic receptor. I. A multivariate analysis of the binding profiles of 14 drugs at 21 native and cloned human receptor subtypes". J Pharmacol Exp Ther. 303 (2): 791–804. doi:10.1124/jpet.102.039867. PMID 12388666. S2CID 6200455.
  12. Newman-Tancredi A, Cussac D, Audinot V, Nicolas JP, De Ceuninck F, Boutin JA, Millan MJ (November 2002). "Differential actions of antiparkinson agents at multiple classes of monoaminergic receptor. II. Agonist and antagonist properties at subtypes of dopamine D(2)-like receptor and alpha(1)/alpha(2)-adrenoceptor". J Pharmacol Exp Ther. 303 (2): 805–14. doi:10.1124/jpet.102.039875. PMID 12388667. S2CID 35238120.
  13. Newman-Tancredi A, Cussac D, Quentric Y, Touzard M, Verrièle L, Carpentier N, Millan MJ (November 2002). "Differential actions of antiparkinson agents at multiple classes of monoaminergic receptor. III. Agonist and antagonist properties at serotonin, 5-HT(1) and 5-HT(2), receptor subtypes". J Pharmacol Exp Ther. 303 (2): 815–22. doi:10.1124/jpet.102.039883. PMID 12388668. S2CID 19260572.
  14. "PDSP Database - UNC". pdsp.unc.edu. Archived from the original on 13 April 2021. Retrieved 15 January 2022.
  15. ADRAC (August 2004). "Cardiac valvulopathy with pergolide". Aust Adv Drug React Bull. 23 (4). Archived from the original on 2007-12-15.
  16. Public Health Advisory - Pergolide (marketed as Permax)
  17. Jähnichen S, Horowski R, Pertz H. ""Pergolide and Cabergoline But not Lisuride Exhibit Agonist Efficacy at Serotonin 5-HT2B Receptors"" (PDF). (515 KiB) Presentation. Retrieved on 2007-03-30.
  18. Schade R, Andersohn F, Suissa S, Haverkamp W, Garbe E (2007). "Dopamine agonists and the risk of cardiac-valve regurgitation". N Engl J Med. 356 (1): 29–38. doi:10.1056/NEJMoa062222. PMID 17202453.
  19. "MedWatch - 2007 Safety Information Alerts. Permax (pergolide) and generic equivalents". U.S. Food and Drug Administration. March 29, 2007. Retrieved 2007-03-30.
  20. Breitenstein C, et al. (2006). "Tonic dopaminergic stimulation impairs associative learning in healthy subjects". Neuropsychopharmacology. 31 (11): 2552–64. doi:10.1038/sj.npp.1301167. PMID 16880771.
  21. "Drug 'caused' gambling addiction" BBC TV 24 Jan. 2008
  22. "Parkinson's Gambler" ITV.com 5 Feb. 2008
  23. "Parkinson's treatment linked to sex, gambling" 'The Age' 4 June 2010
  24. "Archived copy". www.drugs.com. Archived from the original on 7 January 2014. Retrieved 15 January 2022.{{cite web}}: CS1 maint: archived copy as title (link)
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