Wikipedia

Lisuride

Lisuride,sold under the brand nameDoperginamong others, is amonoaminergicmedicationof theergolineclass which is used in the treatment ofParkinson's disease,migraine,andhigh prolactin levels.[1]It is takenby mouth.[1]

Lisuride
Clinical data
Trade namesDopergin, others
Other namesLysuride; Mesorgydin; Methylergol carbamide
AHFS/DrugsInternational Drug Names
Routes of
administration		Oral[1]
Investigational:Subcutaneous implant,transdermal patch[1]
ATC code
Legal status
Legal status
  • BR:Class C1(Other controlled substances)[2]
  • In general: ℞ (Prescription only)
Pharmacokineticdata
Bioavailability10–20%[3]
Protein binding60–70%[3]
MetabolismHepatic
MetabolitesMore than 15 known[3]
Eliminationhalf-life2 hours[3]
ExcretionRenalandbiliaryin equal amounts
Identifiers
  • 1,1-Diethyl-3-(7-methyl-4,6,6a,7,8,9-hexahydro-indolo[4,3-fg]quinolin-9-yl)-urea
CAS Number
PubChemCID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard(EPA)
ECHA InfoCard100.038.099Edit this at Wikidata
Chemical and physical data
FormulaC20H26N4O
Molar mass338.455g·mol−1
3D model (JSmol)
  • [H][C@@]12Cc3c[nH]c4cccc(C1=C[C@H](NC(=O)N(CC)CC)CN2C)c34
  • InChI=1S/C20H26N4O/c1-4-24(5-2)20(25)22-14-10-16-15-7-6-8-17-19(15)13(11-21-17)9-18(16)23(3)12-14/h6-8,10-11,14,18,21H,4-5,9,12H2,1-3H3,(H,22,25)/t14-,18+/m0/s1checkY
  • Key:BKRGVLQUQGGVSM-KBXCAEBGSA-NcheckY
(verify)

Side effectsof lisuride includenauseaand vomiting, dizziness,headache, fatigueordrowsiness, insomniaor sleep, gastrointestinal disturbances such asabdominal painordiarrhea, nasal congestion or runny nose, andhypotension,hallucinationsorconfusion(particularly at higher doses). Rarely, serious side effects such ascardiacorpulmonary fibrosishave been reported with long-term use, but they are extremely uncommon.[3]

Lisuride acts as a mixedagonistandantagonistofdopamine,serotonin,andadrenergic receptors.[1][4][5][6]Activation of specific dopamine receptors is thought to be responsible for its effectiveness in the treatment of Parkinson's disease and ability to suppressprolactinlevels,[1]while interactions with serotonin receptors are thought to be principally involved in its effectiveness formigraine.[7][8]

Medical uses

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Lisuride is used to lowerprolactinand, in low doses, to preventmigraineattacks.[1]The use of lisuride as initialantiparkinsonian medicationforParkinson's diseasehas been advocated, delaying the need forlevodopauntil lisuride becomes insufficient for controlling the parkinsonian symptoms.[1][additional citation(s) needed]Evidence is insufficient to support lisuride in the treatment of advanced Parkinson's disease as an alternative to levodopa orbromocriptine.[9][10]

Side effects

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Side effectsof lisuride includenauseaandlowered blood pressure,among others.[3]

Pharmacology

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Pharmacodynamics

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Lisuride is aligandofdopamine,serotonin,andadrenergic receptorsas well as thehistamine H1receptor.[4]It has sub-nanomolaraffinityfor the dopamineD2,andD3receptors,serotonin5-HT1Aand5-HT1Dreceptors,andα2A-,α2B-,andα2C-adrenergic receptors,and low-nanomolar affinity for the dopamineD1,D4,andD5receptors,serotonin5-HT2A,5-HT2B,and5-HT2Creceptors,α1A-,α1B-,andα1D-adrenergic receptors,and histamine H1receptor.[4][11][12]Lisuride is apartial agonistof the D2,D3,D4,5-HT2A,5-HT2C,5-HT5A,and H1receptors, afull or near-full agonistof the 5-HT1A,5-HT1B,and 5-HT1Dreceptors, and asilent antagonistof the 5-HT2Breceptor and α1A-, α2A-, α2B-, and α2C-adrenergic receptors.[5][6][12][13][14][15]Due to its highly non-selectivepharmacological activity, lisuride is described as a "dirty drug".[1]The effectiveness of lisuride in Parkinson's disease and hyperprolactinemia is thought to be mostly due to activation of dopamine D2receptors.[1]

While lisuride has a similar receptor binding profile to the more well-known and chemically similar ergolinelysergic acid diethylamide(LSD;N,N-diethyllysergamide) and acts as a partial agonist of the serotonin 5-HT2Areceptor likewise,[6]it lacks thepsychedeliceffects of LSD and hence is non-hallucinogenic.[16][1]Research suggests that the lack of psychedelic effects with lisuride arises frombiased agonismof the 5-HT2Areceptor. Stimulation of the 5-HT2Aprotomerwithin the5-HT2A–mGlu2receptor complexevokes psychedelic effects, while these effects do not occur during sole stimulation ofmonomeric5-HT2Areceptors. Accordingly, differentG proteinsare involved.[17][18]Lisuride behaves as an agonist at the 5-HT2Areceptor monomer. Since itcompetitively antagonizesthe effects of LSD, it may be regarded as a protomer antagonist of the 5-HT2A–mGluRheteromer.[19]GPCR oligomersare discrete entities and usually possess properties distinct from their parent monomeric receptors. However, this theory is controversial, and other research has found that 5-HT2A–mGlu2dimers may not be essential for psychedelic effects.[20][21]Lisuride shows weak or noGqpathwayrecruitment and this may be responsible for its non-hallucinogenic nature.[22][23]

Lisuride dose-dependently suppressesprolactinlevels due to its dopaminergic activity.[1][24]As an antagonist of the 5-HT2Breceptor, lisuride has no risk ofcardiac valvulopathyin contrast to related ergolines likepergolideandcabergoline.[1]

Minute amounts of lisuride suppress the firing of dorsal raphe serotonergic neurons, presumably due to agonist activity at 5-HT1Areceptors.[25]Noradrenergic neurons of the locus coeruleus were accelerated by the drug at somewhat higher doses, consistent with α1-adrenergic receptor antagonist activity. Pars compacta dopamine neurons demonstrated a variable response.

Activities of lisuride at various sites[4][5][6][14][26]
Site Affinity (Ki[nM]) Efficacy (Emax[%]) Action
D1 65 ? ?
D2S 0.34 55 Partial agonist
D2L 0.66 21 Partial agonist
D3 0.28 49 Partial agonist
D4 4.6 32 Partial agonist
D5 3.5 ? ?
5-HT1A 0.15 98 Full agonist
5-HT1B 19 85 Partial agonist
5-HT1D 0.98 81 Partial agonist
5-HT2A 2.8 52 Partial agonist
5-HT2B 1.3 0 Silent antagonist
5-HT2C 6.6 75 Partial agonist
5-HT5A ? 11[15] Partial agonist[15]
α1A 5.5 0 Silent antagonist
α1B 17 ? ?
α1D 3.0 ? ?
α2A 0.055 0 Silent antagonist
α2B 0.13 0 Silent antagonist
α2C 0.13 0 Silent antagonist
α2D 0.79 ? ?
β1 68 ? ?
β2 7.9 ? ?
H1 35 ? Partial agonist
M1 >10,000 – –
Notes:All receptors are human except α2D-adrenergic, which is rat (no human counterpart).[4]

Pharmacokinetics

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Absorptionof lisuride from thegastrointestinal tractwithoral administrationis complete.[3]Theabsolute bioavailabilityof lisuride is 10 to 20% due to highfirst-pass metabolism.[3]Theplasma protein bindingof lisuride is 60 to 70%.[3]Peak levelsof lisuride occur 60 to 80 minutes after ingestion with high variability between individuals.[3]Theelimination half-lifeof lisuride is approximately 2 hours.[3]This is shorter than most otherdopamine agonists.[3]Lisuride has more than 15 knownmetabolites.[3]

Chemistry

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Lisuride is described as thefree baseand as the hydrogenmaleatesalt.[27][28][29]

Brominationof lisuride givesbromerguride(2-bromolisuride), which has a "reversed pharmacodynamic profile" compared to that of lisuride.[30]

History

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Lisuride wassynthesizedby Zikán and Semonský at the Research Institute for Pharmacy and Biochemistry at Prague (later SPOFA) as anantimigraine agentanalogous tomethysergideand was described in 1960.[1][31]It was marketed by the early 1970s.[32]

Society and culture

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Generic names

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Lisurideis theINNTooltip International Nonproprietary Nameandlysurideis theBANTooltip British Approved Name.[27][33][28][29]

Brand names

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Lisuride has been sold under brand names including Arolac, Cuvalit, Dopagon, Dopergin, Dopergine, Eunal, Lisenil, Lizenil, Lysenyl, Proclacam, Prolacam, and Revanil.[27][28][29][1]

Availability

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Lisuride was previously more widely available throughout the world,[28][1]but as of 2020 it appears to be marketed only inEgypt,France,Italy,Kuwait,Lebanon,Mexico,New Zealand,andPakistan.[29]Lisuride is not currently available in theUnited States,as the drug was not a commercial success.

Research

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Preliminary clinical research suggests thattransdermal administrationof lisuride may be useful in the treatment ofParkinson's disease.[1]As lisuride has poor bioavailability when taken orally and has a short half-life, continuous transdermal administration offers significant advantages and could make the compound a much more consistent therapeutic agent.[1]Lisuride was under development as atransdermal patchandsubcutaneous implantfor the treatment of Parkinson's disease,restless legs syndrome,anddyskinesiasin the 2000s and 2010s, but development was discontinued.[34][35]

References

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  2. ^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).Archivedfrom the original on 2023-08-03.Retrieved2023-08-16.
  3. ^abcdefghijklm"DA agonists -- ergot derivatives: lisuride: management of Parkinson's disease".Movement Disorders.17 Suppl 4 (S4):S74 –S78.2002.doi:10.1002/mds.5565.PMID12211144.S2CID79230929.
  4. ^abcdeMillan 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.PMID12388666.S2CID6200455.
  5. ^abcNewman-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.PMID12388667.S2CID35238120.
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  20. ^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.PMC10700551.PMID36932180.This group has also reported that a heterodimeric complex between mGluR2 metabotropic glutamate and 5-HT2A receptors may be responsible for these actions [108–110]. Others have provided data suggesting the complex as such is not essential for the actions of psychedelics at 5-HT2A receptors [111].
  21. ^López-Giménez JF, González-Maeso J (2017). "Hallucinogens and Serotonin 5-HT2A Receptor-Mediated Signaling Pathways".Behavioral Neurobiology of Psychedelic Drugs.Current Topics in Behavioral Neurosciences. Vol. 36. Berlin, Heidelberg: Springer Berlin Heidelberg. pp.45–73.doi:10.1007/7854_2017_478.ISBN978-3-662-55878-2.PMC5756147.PMID28677096.Because DOI-induced head-twitch behavior is not rescued in mGlu2 knockout mice over-expressing mGlu2ΔTM4N [a mGlu2/mGlu3 chimeric construct that does not form heteromers with the 5-HT2A receptor (Gonzalez-Maeso et al. 2008; Fribourg et al. 2011)] in frontal cortex (Moreno et al. 2012), these findings suggest that the 5-HT2A-mGlu2 receptor complex is critical for the hallucinogen-like behaviors induced by 5-HT2A receptor agonists (Figs. 6 and 7). [...] However, further investigation of this heteromeric receptor complex is definitely necessary because the functional significance of GPCR homo- and heteromerization remains a controversial topic (Bouvier and Hebert 2014; Lambert and Javitch 2014) [in addition, see: Delille et al. (2012), Frederick et al. (2015)].
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  31. ^Zikán V, Semonský M (1960). "Mutterkornalkaloide XVI. Einige N-(D-6-methylisoergolenyl-8)-, N-(D-6-methylergolenyl-8)- und N-(D-6-methylergolin(I)-yl-8)-N'-substituierte harnstoffe".Collection of Czechoslovak Chemical Communications.25(7):1922–1928.doi:10.1135/cccc19601922.ISSN0010-0765.
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  34. ^"Lisuride - Axxonis Pharma".AdisInsight.Springer Nature Switzerland AG.
  35. ^"Lisuride implant - Titan Pharmaceuticals".AdisInsight.Springer Nature Switzerland AG.
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