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 synthesis 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 names	Permax, Prascend (veterinary), others
Other names	8β-[(Methylthio)methyl]-6-propylergoline
AHFS/Drugs.com	Monograph
Pregnancy category	B
Routes of administration	Oral
ATC code	N04BC02 (WHO)
Legal status
Legal status	BR: Class C1 (Other controlled substances)[1] CA: ℞-only US: WARNING[2] Veterinary use only, withdrawn for human use
Pharmacokinetic data
Protein binding	90%
Metabolism	Extensively Hepatic
Elimination half-life	27 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	66104-22-1 Y
PubChem CID	47811
IUPHAR/BPS	48
DrugBank	DB01186 Y
ChemSpider	43503 Y
UNII	24MJ822NZ9
KEGG	D08339 Y
ChEBI	CHEBI:63617 N
ChEMBL	ChEMBL531 Y
CompTox Dashboard (EPA)	DTXSID2023438
ECHA InfoCard	100.241.322
Chemical and physical data
Formula	C19H26N2S
Molar mass	314.49 g·mol−1
3D model (JSmol)	Interactive image
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It was patented in 1978^[3] and approved for medical use in 1989.^[4] In 2007, pergolide was withdrawn from the U.S. market for human use after several published studies revealed a link between the drug and increased rates of valvular heart disease.^[5] However,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.^[6]

Medical uses

Pergolide is no longer 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.^{[citation needed]}

Pergolide is available for veterinary use. Under the trade name Prascend, manufactured by Boehringer Ingelheim,^[7] 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-HT_1A, 5-HT_1B, 5-HT_2A, 5-HT_2B, and 5-HT_2C 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.^[8] 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-HT_2A receptors.^[9][10] However, other sources have stated that the drug is non-hallucinogenic.^[11] It has been associated with cardiac valvulopathy due to activation of 5-HT_2B receptors.^[12]

Activities of pergolide at various sites^{[13][14][15][16]}

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).[13][16]

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.^[17] 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.^[18] 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-HT_2B serotonin receptors of cardiac myocytes, causing proliferative valve disease by the same mechanism as ergotamine, methysergide, fenfluramine, and other serotonin 5-HT_2B 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.^[19] In January 2007, cabergoline (Dostinex) was also reported to be associated with valvular proliferation heart damage.^[20] 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.^[21]

Pergolide has also been shown to impair associative learning.^[22]

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.^[23][24] 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^[25] 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.^[26]

Research

Pergolide has been studied in the treatment of social anxiety disorder in one small study but was found to be ineffective.^[27][28]

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. "FDA-sourced list of all drugs with black box warnings (Use Download Full Results and View Query links.)". nctr-crs.fda.gov. FDA. Retrieved 22 Oct 2023.
3. 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
4. Fischer J, Ganellin CR (2006). Analogue-based Drug Discovery. John Wiley & Sons. p. 533. ISBN 9783527607495.
5. "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)
6. Forney B. "Pergolide for Veterinary Use".
7. "Prascend for Horses". Boehringer Ingelheim. Valley Vet Supply.
8. 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.
9. 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.
10. 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". European Journal of Pharmacology. 594 (1–3): 32–38. doi:10.1016/j.ejphar.2008.07.040. PMID 18703043.
11. 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. PMID 36932180.
12. 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.
13. 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.
14. 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". The Journal of Pharmacology and Experimental Therapeutics. 303 (2): 805–814. doi:10.1124/jpet.102.039875. PMID 12388667. S2CID 35238120.
15. 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". The Journal of Pharmacology and Experimental Therapeutics. 303 (2): 815–822. doi:10.1124/jpet.102.039883. PMID 12388668. S2CID 19260572.
16. "PDSP Database - UNC". pdsp.unc.edu. Archived from the original on 13 April 2021. Retrieved 15 January 2022.
17. ADRAC (August 2004). "Cardiac valvulopathy with pergolide". Aust Adv Drug React Bull. 23 (4). Archived from the original on 2007-12-15.
18. "Pergolide (marketed as Permax)". Public Health Advisory.
19. Jähnichen S, Horowski R, Pertz H. ""Pergolide and Cabergoline But not Lisuride Exhibit Agonist Efficacy at Serotonin 5-HT_2B Receptors"" (PDF). (515 KiB) Presentation. Retrieved on 2007-03-30.
20. 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.
21. "MedWatch - 2007 Safety Information Alerts. Permax (pergolide) and generic equivalents". U.S. Food and Drug Administration. March 29, 2007. Retrieved 2007-03-30.
22. 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.
23. "Drug 'caused' gambling addiction". BBC TV. 24 January 2008.
24. "Parkinson's Gambler". ITV.com. 5 February 2008.
25. "Parkinson's treatment linked to sex, gambling". The Age. 4 June 2010.
26. "Pergolide - Drugs.com". www.drugs.com. Archived from the original on 7 January 2014. Retrieved 15 January 2022.
27. 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 Opin Investig Drugs. 9 (10): 2215–2231. doi:10.1517/13543784.9.10.2215. PMID 11060802.
28. Villarreal G, Johnson MR, Rubey R, Lydiard RB, Ballanger JC (2000). "Treatment of social phobia with the dopamine agonist pergolide". Depress Anxiety. 11 (1): 45–47. doi:10.1002/(sici)1520-6394(2000)11:1<45::aid-da8>3.0.co;2-8. PMID 10723636.