Wikipedia:WikiProject Chemicals/Chembox validation/VerifiedDataSandbox and Pergolide: Difference between pages

{{Short description|Dopamine agonist medication}}

| Verifiedfields = changed

| verifiedrevid = 464199003

| image = Pergolide.svg

| width = 200

| alt =

| tradename = Permax, Prascend (veterinary), others

| legal_BR = C1

| legal_BR_comment = <ref>{{Cite web |author=Anvisa |author-link=Brazilian Health Regulatory Agency |date=2023-03-31 |title=RDC Nº 784 - Listas de Substâncias Entorpecentes, Psicotrópicas, Precursoras e Outras sob Controle Especial |trans-title=Collegiate Board Resolution No. 784 - Lists of Narcotic, Psychotropic, Precursor, and Other Substances under Special Control|url=https://www.in.gov.br/en/web/dou/-/resolucao-rdc-n-784-de-31-de-marco-de-2023-474904992 |url-status=live |archive-url=https://web.archive.org/web/20230803143925/https://www.in.gov.br/en/web/dou/-/resolucao-rdc-n-784-de-31-de-marco-de-2023-474904992 |archive-date=2023-08-03 |access-date=2023-08-16 |publisher=[[Diário Oficial da União]] |language=pt-BR |publication-date=2023-04-04}}</ref>

| legal_CA = Rx-only

| legal_CA_comment =

| legal_US =

| legal_US_comment = Veterinary use only, withdrawn for human use

| routes_of_administration = [[Oral administration|Oral]]

| bioavailability =

| metabolism = Extensively Hepatic

| excretion =

| IUPAC_name = (6a''R'',9''R'',10a''R'')-9-(methylthiomethyl)-7-propyl-4,6,6a,7,8,9,10,10a-octahydroindolo[4,3-''fg'']quinoline

| ChEBI_Ref = {{ebicite|changed|EBI}}

| ChEBI = 63617

| synonyms = 8β-[(Methylthio)methyl]-6-propylergoline

| C=19 | H=26 | N=2 | S=1

| SMILES = [H][C@]12C[C@@H](CSC)CN(CCC)[C@]1([H])Cc3c[nH]c4cccc2c34

'''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 [[therapy|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.

<!-- Society and culture -->

It was patented in 1978<ref name="US4166182A">{{cite patent |country=US |number=4166182A |status=patent |title=6-n-propyl-8-methoxymethyl or methylmercaptomethylergolines and related compounds |pubdate=1979-08-28 |gdate=1979-08-28 |fdate=1978-02-08 |pridate=1978-02-08 |invent1=Edmund C. Kornfeld |invent2=Nicholas J. Bach |assign1=Eli Lilly and Co}}</ref> and approved for medical use in 1989.<ref name=Fis2006>{{cite book | vauthors = Fischer J, Ganellin CR |title=Analogue-based Drug Discovery |date=2006 |publisher=John Wiley & Sons |isbn=9783527607495 |page=533 |url=https://books.google.com/books?id=FjKfqkaKkAAC&pg=PA533 |language=en}}</ref> 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]].<ref>{{cite web | url = https://www.fda.gov/cder/drug/advisory/pergolide.htm | work = FDA Public Health Advisory | title = Pergolide (marketed as Permax) | access-date = 2019-12-16 | archive-date = 2007-04-08 | archive-url = https://web.archive.org/web/20070408111551/https://www.fda.gov/cder/drug/advisory/pergolide.htm | url-status = bot: unknown }}</ref> 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.<ref name = "Forney">{{Cite web | vauthors = Forney B |url=http://www.wedgewoodpetrx.com/learning-center/professional-monographs/pergolide-for-veterinary-use.html|title=Pergolide for Veterinary Use}}</ref>

==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|date=March 2016}}

Pergolide is available for veterinary use. Under the trade name Prascend, manufactured by [[Boehringer Ingelheim]],<ref>{{Cite web|url=http://www.valleyvet.com/ct_detail.html?pgguid=e0f4888c-86de-4ce9-9013-6d947df697a8&gas=pergolide%20mesylate|title=Prascend for Horses | work = Boehringer Ingelheim | publisher = Valley Vet Supply }}</ref> it is commonly used for the treatment of [[pituitary adenoma|pituitary hyperplasia]] at the [[pars intermedia]] or [[Pituitary Pars Intermedia Dysfunction|Equine Cushing's Syndrome]] (ECS) in horses.<ref name = "Forney" />

==Pharmacology==

===Pharmacodynamics===

Pergolide acts as an agonist of [[dopamine receptor|dopamine]] [[Dopamine receptor D2|D₂]] and [[Dopamine receptor D1|D₁]] and [[serotonin receptor|serotonin]] [[5-HT1A|5-HT_1A]], [[5-HT1B|5-HT_1B]], [[5-HT2A|5-HT_2A]], [[5-HT2B|5-HT_2B]], and [[5-HT2C|5-HT_2C]] [[receptor (biochemistry)|receptor]]s. 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 (pharmacology)|affinity]] and is one of the most potent D₁ receptor agonists of the [[dopamine receptor agonist]]s that are clinically available.<ref name="McClureHarvey2010">{{cite journal | vauthors = McClure MM, Harvey PD, Goodman M, Triebwasser J, New A, Koenigsberg HW, Sprung LJ, Flory JD, Siever LJ | display-authors = 6 | title = Pergolide treatment of cognitive deficits associated with schizotypal personality disorder: continued evidence of the importance of the dopamine system in the schizophrenia spectrum | journal = Neuropsychopharmacology | volume = 35 | issue = 6 | pages = 1356–1362 | date = May 2010 | pmid = 20130535 | pmc = 3055340 | doi = 10.1038/npp.2010.5 }}</ref> 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.<ref name="pmid19925619">{{cite journal | vauthors = Gillman PK | title = Triptans, serotonin agonists, and serotonin syndrome (serotonin toxicity): a review | journal = Headache | volume = 50 | issue = 2 | pages = 264–272 | date = February 2010 | pmid = 19925619 | doi = 10.1111/j.1526-4610.2009.01575.x | s2cid = 221752556 | doi-access = free }}</ref><ref name="pmid18703043">{{cite journal | vauthors = Cussac D, Boutet-Robinet E, Ailhaud MC, Newman-Tancredi A, Martel JC, Danty N, Rauly-Lestienne I | title = 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 | journal = European Journal of Pharmacology | volume = 594 | issue = 1–3 | pages = 32–38 | date = October 2008 | pmid = 18703043 | doi = 10.1016/j.ejphar.2008.07.040 }}</ref> However, other sources have stated that the drug is non-hallucinogenic.<ref name="GumpperRoth2024">{{cite journal | vauthors = Gumpper RH, Roth BL | title = Psychedelics: preclinical insights provide directions for future research | journal = Neuropsychopharmacology | volume = 49 | issue = 1 | pages = 119–127 | date = January 2024 | pmid = 36932180 | doi = 10.1038/s41386-023-01567-7 | url = }}</ref> It has been associated with [[cardiac valvulopathy]] due to activation of 5-HT_2B receptors.<ref name="pmid24361689">{{cite journal | vauthors = Cavero I, Guillon JM | title = Safety Pharmacology assessment of drugs with biased 5-HT(2B) receptor agonism mediating cardiac valvulopathy | journal = Journal of Pharmacological and Toxicological Methods | volume = 69 | issue = 2 | pages = 150–161 | date = 2014 | pmid = 24361689 | doi = 10.1016/j.vascn.2013.12.004 }}</ref>

{| class="wikitable"

|+ {{Nowrap|Activities of pergolide at various sites<ref name="pmid12388666">{{cite journal | vauthors = Millan MJ, Maiofiss L, Cussac D, Audinot V, Boutin JA, Newman-Tancredi A | title = 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 | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 303 | issue = 2 | pages = 791–804 | date = November 2002 | pmid = 12388666 | doi = 10.1124/jpet.102.039867 | s2cid = 6200455 }}</ref><ref name="pmid12388667">{{cite journal | vauthors = Newman-Tancredi A, Cussac D, Audinot V, Nicolas JP, De Ceuninck F, Boutin JA, Millan MJ | title = 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 | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 303 | issue = 2 | pages = 805–814 | date = November 2002 | pmid = 12388667 | doi = 10.1124/jpet.102.039875 | s2cid = 35238120 }}</ref><ref name="pmid12388668">{{cite journal | vauthors = Newman-Tancredi A, Cussac D, Quentric Y, Touzard M, Verrièle L, Carpentier N, Millan MJ | title = 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 | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 303 | issue = 2 | pages = 815–822 | date = November 2002 | pmid = 12388668 | doi = 10.1124/jpet.102.039883 | s2cid = 19260572 }}</ref><ref name="PDSPKiDatabase">{{cite web |url=https://pdsp.unc.edu/databases/pdsp.php?testFreeRadio=testFreeRadio&testLigand=Pergolide&doQuery=Submit+Query |title=PDSP Database - UNC |website=pdsp.unc.edu |access-date=15 January 2022 |archive-url=https://web.archive.org/web/20210413033753/https://pdsp.unc.edu/databases/pdsp.php?testFreeRadio=testFreeRadio&testLigand=Pergolide&doQuery=Submit+Query |archive-date=13 April 2021 |url-status=dead}}</ref>}}

! Site

! Affinity (K_i [nM])

! Efficacy (E_max [%])

! Action

|-

| [[D1 receptor|D₁]]

| 339

| ?

| ?

|-

| [[D2S receptor|D_2S]]

| 32

| 112

| Full agonist

|-

| [[D2L receptor|D_2L]]

| 26

| 52

| Partial agonist

|-

| [[D3 receptor|D₃]]

| 5.5

| 71

| Partial agonist

|-

| [[D4 receptor|D₄]]

| 59

| 56

| Partial agonist

|-

| [[D5 receptor|D₅]]

| 33

| ?

| ?

|-

| [[5-HT1A receptor|5-HT_1A]]

| 1.9

| 63

| Partial agonist

|-

| [[5-HT1B receptor|5-HT_1B]]

| 282

| 90

| Partial agonist

|-

| [[5-HT1D receptor|5-HT_1D]]

| 13

| 86

| Partial agonist

|-

| [[5-HT2A receptor|5-HT_2A]]

| 8.3

| 103

| Full agonist

|-

| [[5-HT2B receptor|5-HT_2B]]

| 7.1

| 113

| Full agonist

|-

| [[5-HT2C receptor|5-HT_2C]]

| 295

| 87

| Partial agonist

|-

| [[5-HT6 receptor|5-HT₆]]

| 30

| ?

| ?

|-

| [[5-HT7 receptor|5-HT₇]]

| 1.0–18

| ?

| ?

|-

| [[α1A-Adrenergic receptor|α_1A]]

| 1,047

| ?

| ?

|-

| [[α1B-Adrenergic receptor|α_1B]]

| 692

| ?

| ?

|-

| [[α1D-Adrenergic receptor|α_1D]]

| 295

| ?

| ?

|-

| [[α2A-Adrenergic receptor|α_2A]]

| 50

| 31

| Partial agonist

|-

| [[α2B-Adrenergic receptor|α_2B]]

| 32

| 70

| Partial agonist

|-

| [[α2C-Adrenergic receptor|α_2C]]

| 68

| 16

| Partial agonist

|-

| [[α2D-Adrenergic receptor|α_2D]]

| 692

| ?

| ?

|-

| [[β1-Adrenergic receptor|β₁]]

| >10,000

| –

| –

|-

| [[β2-Adrenergic receptor|β₂]]

| >10,000

| –

| –

|-

| [[H1 receptor|H₁]]

| 1,698

| ?

| ?

|-

| [[Muscarinic acetylcholine receptor M1|M₁]]

| >10,000

| –

| –

|-

| [[Sigma-1 receptor|σ₁]]

| >10,000

| –

| –

|-

| [[Sigma-2 receptor|σ₂]]

| 923

| ?

| ?

|- class="sortbottom"

| colspan="4" style="width: 1px; background-color:#eaecf0; text-align: center;" | '''Notes:''' All receptors are human except α_2D-adrenergic, which is rat (no human counterpart), and 5-HT₆, 5-HT₇, σ₁, and σ₂, which are all rodent (rat or guinea pig).<ref name="pmid12388666" /><ref name="PDSPKiDatabase" />

|}

==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]].<ref>{{cite journal | url = http://www.tga.gov.au/adr/aadrb/aadr0408.htm | date = August 2004 | title = Cardiac valvulopathy with pergolide | author = ADRAC | journal = Aust Adv Drug React Bull | volume = 23 | issue = 4 | author-link = Adverse Drug Reactions Advisory Committee | url-status = dead | archive-url = https://web.archive.org/web/20071215145351/http://www.tga.gov.au/adr/aadrb/aadr0408.htm | archive-date = 2007-12-15 }}</ref> 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.<ref>{{cite web | url = https://www.fda.gov/Drugs/DrugSafety/PublicHealthAdvisories/ucm051285.html | work = Public Health Advisory | title = Pergolide (marketed as Permax) }}</ref> 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.<ref>Jähnichen S, Horowski R, Pertz H. {{cite web|url= http://userpage.fu-berlin.de/~hpertz/Presentation001.pdf |title="Pergolide and Cabergoline But not Lisuride Exhibit Agonist Efficacy at Serotonin 5-HT_2B Receptors". }}&nbsp;{{small|(515&nbsp;[[Kibibyte|KiB]])}} Presentation. Retrieved on 2007-03-30.</ref> In January 2007, [[cabergoline]] (Dostinex) was also reported to be associated with valvular proliferation heart damage.<ref>{{cite journal | vauthors = Schade R, Andersohn F, Suissa S, Haverkamp W, Garbe E | title = Dopamine agonists and the risk of cardiac-valve regurgitation | journal = The New England Journal of Medicine | volume = 356 | issue = 1 | pages = 29–38 | date = January 2007 | pmid = 17202453 | doi = 10.1056/NEJMoa062222 | doi-access = free }}</ref> 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.<ref name="FDAwithdraw">{{cite web | url = https://www.fda.gov/medwatch/safety/2007/safety07.htm#Pergolide | title = MedWatch - 2007 Safety Information Alerts. Permax (pergolide) and generic equivalents | publisher = U.S. [[Food and Drug Administration]] | date = March 29, 2007 | access-date = 2007-03-30}}</ref>

Pergolide has also been shown to impair associative learning.<ref>{{cite journal | vauthors = Breitenstein C, Korsukewitz C, Flöel A, Kretzschmar T, Diederich K, Knecht S | title = Tonic dopaminergic stimulation impairs associative learning in healthy subjects | journal = Neuropsychopharmacology | volume = 31 | issue = 11 | pages = 2552–2564 | date = November 2006 | pmid = 16880771 | doi = 10.1038/sj.npp.1301167 | doi-access = free }}</ref>

===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]].<ref>{{cite web | url = http://news.bbc.co.uk/1/hi/england/merseyside/7207850.stm | title = Drug 'caused' gambling addiction | work = BBC TV | date = 24 January 2008 }}</ref><ref>{{cite web | url = http://www.itv.com/Lifestyle/ThisMorning/Health/Parkinsonsgambler/default.html | title = Parkinson's Gambler | work = ITV.com | date = 5 February 2008 }}</ref> 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]]<ref>{{cite web | url = http://www.theage.com.au/national/parkinsons-treatment-linked-to-sex-gambling-20100603-x6y7.html | title = Parkinson's treatment linked to sex, gambling | work = The Age | date = 4 June 2010 }}</ref> 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.<ref name="Drugs.com">{{cite web |url=http://www.drugs.com/international/pergolide.html |title=Pergolide - Drugs.com |website=www.drugs.com |access-date=15 January 2022 |archive-url=https://web.archive.org/web/20140107030628/http://www.drugs.com/international/pergolide.html |archive-date=7 January 2014 |url-status=dead}}</ref>

==Research==

Pergolide has been studied in the treatment of [[social anxiety disorder]] in one small study but was found to be ineffective.<ref name="vanAmeringenMancini2000">{{cite journal | vauthors = van Ameringen M, Mancini C, Farvolden P, Oakman J | title = Drugs in development for social anxiety disorder: more to social anxiety than meets the SSRI | journal = Expert Opin Investig Drugs | volume = 9 | issue = 10 | pages = 2215–2231 | date = October 2000 | pmid = 11060802 | doi = 10.1517/13543784.9.10.2215 | url = }}</ref><ref name="VillarrealJohnsonRubey2000">{{cite journal | vauthors = Villarreal G, Johnson MR, Rubey R, Lydiard RB, Ballanger JC | title = Treatment of social phobia with the dopamine agonist pergolide | journal = Depress Anxiety | volume = 11 | issue = 1 | pages = 45–47 | date = 2000 | pmid = 10723636 | doi = 10.1002/(sici)1520-6394(2000)11:1<45::aid-da8>3.0.co;2-8 | url = | doi-access = free }}</ref>

== References ==

{{Reflist}}

{{Navboxes

| title = [[Medical use]]s

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| list1 =

{{Antiparkinson}}

{{Prolactin inhibitors and anti-inflammatory products for vaginal administration}}

{{Hallucinogens}}

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{{Navboxes

| title = [[Pharmacodynamics]]

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| list1 =

{{Adrenergic receptor modulators}}

{{Dopamine receptor modulators}}

{{Prolactin receptor modulators}}

{{Serotonin receptor modulators}}

}}

{{Ergolines}}

[[Category:5-HT2B agonists]]

[[Category:D2-receptor agonists]]

[[Category:D3 receptor agonists]]

[[Category:D4 receptor agonists]]

[[Category:Dopamine receptor modulators]]

[[Category:Equine medications]]

[[Category:Ergolines]]

[[Category:Non-hallucinogenic 5-HT2A receptor agonists]]

[[Category:Prolactin inhibitors]]

[[Category:Thioethers]]

[[Category:Withdrawn drugs]]

[[Category:Cardiotoxins]]