Pergolide

Pergolide
Clinical data
Trade namesPermax, Prascend (veterinary), others
Other names8β-[(Methylthio)methyl]-6-propylergoline; 8b-[(Methylsulfanyl)methyl]-6-propylergoline
AHFS/Drugs.comMonograph
Pregnancy
category
  • B
Routes of
administration		Oral
Drug classDopamine receptor agonist; Antiparkinsonian agent
ATC code
Legal status
Legal status
  • BR: Class C1 (Other controlled substances)
  • CA: ℞-only
  • US: Veterinary use only, withdrawn for human use
Pharmacokinetic data
Protein binding90%
MetabolismExtensively hepatic[citation needed]
Elimination half-life27 hours[citation needed]
Identifiers
  • (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 Edit this at Wikidata
Chemical and physical data
FormulaC19H26N2S
Molar mass314.49 g·mol−1
3D model (JSmol)
  • [H][C@]12C[C@@H](CSC)CN(CCC)[C@]1([H])Cc3c[nH]c4cccc2c34
  • 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 checkY
  • Key:YEHCICAEULNIGD-MZMPZRCHSA-N checkY
 X markNcheckY (what is this?)  (verify)

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 synthesis in the substantia nigra of the brain. Pergolide acts on many of the same receptors as dopamine to increase receptor activity.

It was patented in 1978 and approved for medical use in 1989. In 2007, pergolide was withdrawn from the U.S. market for human use after several published studies revealed a link between the drug and increased rates of valvular heart disease. 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.

Medical uses

Pergolide is no longer available for use by humans in the United States, however, it is still used in various other countries, such as in the EU, where it is only recommended for patients who cannot take other treatments.[citation needed]

Pergolide has also been tested for use in treatment of restless leg syndrome and hyperprolactinemia.

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

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. 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 has been said to be hallucinogenic due to activation of 5-HT2A receptors. However, other sources have stated that the drug is non-hallucinogenic. It has been associated with cardiac valvulopathy due to activation of 5-HT2B receptors.

Activities of pergolide at various sites
Site Affinity (pKi [nM]) Efficacy (Emax [%]) Action
D1 6.47 ± 0.04 ? ?
D2S 7.85–8.30 90–112 Full agonist
D2L 7.59–7.80 52–95 Partial to full agonist
D3 0.9 71 Partial agonist
D4 7.23 ± 0.09 56 Partial agonist
D5 7.48 ± 0.21 ? ?
5-HT1A 8.72 ± 0.13 63 Partial agonist
5-HT1B 6.55 ± 0.10 90 Partial agonist
5-HT1D 7.88 ± 0.11 86 Partial agonist
5-HT2A 7.92–8.08 24–103 Partial to full agonist
5-HT2B 8.15–8.42 74–113 Partial to full agonist
5-HT2C 6.53 ± 0.06 87 Partial agonist
5-HT6 30 ? ?
5-HT7 1.0–18 ? ?
α1A 5.98 ± 0.11 ? ?
α1B 6.16 ± 0.08 ? ?
α1D 6.53 ± 0.19 ? ?
α2A 5.39 ± 0.29 31 Partial agonist
α2B 7.30 ± 0.09 70 Partial agonist
α2C 7.49 ± 0.8 16 Partial agonist
α2D 7.17 ± 0.01 ? ?
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).

Side effects

In 2003, pergolide was reported to be associated with a form of heart disease called cardiac fibrosis. In March 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. This damage 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. Among similar antiparkinsonian drugs, cabergoline, but not lisuride, exhibit this same type of serotonin receptor binding and, in January 2007, cabergoline (Dostinex) was also reported to be associated with valvular proliferation heart damage.

Pergolide has also been shown to impair associative learning, and can rarely cause Raynaud's phenomenon.

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. 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 problems they claim are the result of the drug's side effects.

Chemistry

Analogues

Analogues of pergolide include LY-116467 (LY-062, 6-methylpergolide), LY-158A (6-ethylpergolide), and tiomergine (CF 25-397), among others.

Society and culture

Brand names

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

Research

Pergolide has been studied in the treatment of social anxiety disorder in one small study but was found to be ineffective.

See also

References

  1. ↑ Anvisa (2023-03-31). "RDC Nº 784 - Listas de Substâncias Entorpecentes, Psicotrópicas, Precursoras e Outras sob Controle Especial" [Collegiate Board Resolution No. 784 - Lists of Narcotic, Psychotropic, Precursor, and Other Substances under Special Control] (in Brazilian Portuguese). Diário Oficial da União (published 2023-04-04). Archived from the original on 2023-08-03. Retrieved 2023-08-16.
  2. ↑ US patent 4166182A, Kornfeld EC, Bach NJ, "6-n-propyl-8-methoxymethyl or methylmercaptomethylergolines and related compounds", published 1979-08-28, issued 1979-08-28, assigned to Eli Lilly and Co
  3. ↑ Fischer J, Ganellin CR (2006). Analogue-based Drug Discovery. John Wiley & Sons. p. 533. ISBN 978-3-527-60749-5.
  4. ↑ "Pergolide (marketed as Permax)". FDA Public Health Advisory. Archived from the original on 2007-04-08. Retrieved 2019-12-16.{{cite web}}: CS1 maint: bot: original URL status unknown (link)
  5. 1 2 Forney B. "Pergolide for Veterinary Use".
  6. ↑ "Ergot-derived dopamine agonists - referral | European Medicines Agency (EMA)". www.ema.europa.eu. 2008-06-26. Retrieved 2026-05-03.
  7. ↑ Trenkwalder C, Hundemer HP, Lledo A, Swieca J, Polo O, Wetter TC, et al. (April 2004). "Efficacy of pergolide in treatment of restless legs syndrome: the PEARLS Study". Neurology. 62 (8): 1391–1397. doi:10.1212/01.WNL.0000124465.20878.84. PMID 15111679.
  8. ↑ Kletzky OA, Borenstein R, Mileikowsky GN (February 1986). "Pergolide and bromocriptine for the treatment of patients with hyperprolactinemia". American Journal of Obstetrics and Gynecology. 154 (2): 431–435. doi:10.1016/0002-9378(86)90685-x. PMID 3080892.
  9. ↑ "Prascend for Horses". Boehringer Ingelheim. Valley Vet Supply.
  10. ↑ McClure MM, Harvey PD, Goodman M, Triebwasser J, New A, Koenigsberg HW, et al. (May 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. PMC 3055340. PMID 20130535.
  11. ↑ Gillman PK (February 2010). "Triptans, serotonin agonists, and serotonin syndrome (serotonin toxicity): a review". Headache. 50 (2): 264–272. doi:10.1111/j.1526-4610.2009.01575.x. PMID 19925619. S2CID 221752556.
  12. ↑ Cussac D, Boutet-Robinet E, Ailhaud MC, Newman-Tancredi A, Martel JC, Danty N, et al. (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". European Journal of Pharmacology. 594 (1–3): 32–38. doi:10.1016/j.ejphar.2008.07.040. PMID 18703043.
  13. ↑ Gumpper RH, Roth BL (January 2024). "Psychedelics: preclinical insights provide directions for future research". Neuropsychopharmacology. 49 (1): 119–127. doi:10.1038/s41386-023-01567-7. PMC 10700551. PMID 36932180.
  14. ↑ Cavero I, Guillon JM (2014). "Safety Pharmacology assessment of drugs with biased 5-HT(2B) receptor agonism mediating cardiac valvulopathy". Journal of Pharmacological and Toxicological Methods. 69 (2): 150–161. doi:10.1016/j.vascn.2013.12.004. PMID 24361689.
  15. 1 2 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". The Journal of Pharmacology and Experimental Therapeutics. 303 (2): 791–804. doi:10.1124/jpet.102.039867. PMID 12388666. S2CID 6200455.
  16. ↑ Newman-Tancredi A, Cussac D, Audinot V, Nicolas JP, De Ceuninck F, Boutin JA, et al. (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". The Journal of Pharmacology and Experimental Therapeutics. 303 (2): 805–814. doi:10.1124/jpet.102.039875. PMID 12388667. S2CID 35238120.
  17. ↑ Newman-Tancredi A, Cussac D, Quentric Y, Touzard M, Verrièle L, Carpentier N, et al. (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". The Journal of Pharmacology and Experimental Therapeutics. 303 (2): 815–822. doi:10.1124/jpet.102.039883. PMID 12388668. S2CID 19260572.
  18. ↑ Görnemann T, Hübner H, Gmeiner P, Horowski R, Latté KP, Flieger M, et al. (March 2008). "Characterization of the molecular fragment that is responsible for agonism of pergolide at serotonin 5-Hydroxytryptamine2B and 5-Hydroxytryptamine2A receptors". J Pharmacol Exp Ther. 324 (3): 1136–1145. doi:10.1124/jpet.107.133165. PMID 18096760.
  19. 1 2 "PDSP Database - UNC". pdsp.unc.edu. Archived from the original on 13 April 2021. Retrieved 15 January 2022.
  20. ↑ Millan MJ, Maiofiss L, Cussac D, Audinot V, Boutin JA, Newman-Tancredi A (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". The Journal of Pharmacology and Experimental Therapeutics. 303 (2): 791–804. doi:10.1124/jpet.102.039867. PMID 12388666.
  21. ↑ ADRAC (August 2004). "Cardiac valvulopathy with pergolide". Aust Adv Drug React Bull. 23 (4). Archived from the original on 2007-12-15.
  22. ↑ "Pergolide (marketed as Permax)". Public Health Advisory. Archived from the original on June 22, 2009.
  23. ↑ "MedWatch - 2007 Safety Information Alerts. Permax (pergolide) and generic equivalents". U.S. Food and Drug Administration. March 29, 2007. Archived from the original on January 10, 2007. Retrieved 2007-03-30.
  24. ↑ 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.
  25. ↑ Schade R, Andersohn F, Suissa S, Haverkamp W, Garbe E (January 2007). "Dopamine agonists and the risk of cardiac-valve regurgitation". The New England Journal of Medicine. 356 (1): 29–38. doi:10.1056/NEJMoa062222. PMID 17202453.
  26. ↑ Breitenstein C, Korsukewitz C, Flöel A, Kretzschmar T, Diederich K, Knecht S (November 2006). "Tonic dopaminergic stimulation impairs associative learning in healthy subjects". Neuropsychopharmacology. 31 (11): 2552–2564. doi:10.1038/sj.npp.1301167. PMID 16880771.
  27. ↑ "Drug 'caused' gambling addiction". BBC TV. 24 January 2008.
  28. ↑ "Parkinson's Gambler". ITV.com. 5 February 2008.
  29. ↑ Hagan K (4 June 2010). "Parkinson's treatment linked to sex, gambling". The Age.
  30. ↑ "Pergolide". Drugs.com. Archived from the original on 7 January 2014. Retrieved 15 January 2022.
  31. ↑ van Ameringen M, Mancini C, Farvolden P, Oakman J (October 2000). "Drugs in development for social anxiety disorder: more to social anxiety than meets the SSRI". Expert Opinion on Investigational Drugs. 9 (10): 2215–2231. doi:10.1517/13543784.9.10.2215. PMID 11060802.
  32. ↑ Villarreal G, Johnson MR, Rubey R, Lydiard RB, Ballanger JC (2000). "Treatment of social phobia with the dopamine agonist pergolide". Depression and Anxiety. 11 (1): 45–47. doi:10.1002/(sici)1520-6394(2000)11:1<45::aid-da8>3.0.co;2-8. PMID 10723636.