Chemistry:Lisuride

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Short description: Chemical compound
Lisuride
Lisuride.svg
Clinical data
Trade namesDopergin, others
Other namesLysuride; Mesorgydin; Methylergol carbamide
AHFS/Drugs.comInternational 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)
  • In general: ℞ (Prescription only)
Pharmacokinetic data
Bioavailability10–20%[2]
Protein binding60–70%[2]
MetabolismHepatic
MetabolitesMore than 15 known[2]
Elimination half-life2 hours[2]
ExcretionRenal and biliary in equal amounts
Identifiers
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
Chemical and physical data
FormulaC20H26N4O
Molar mass338.455 g·mol−1
3D model (JSmol)
  (verify)

Lisuride, sold under the brand name Dopergin among others, is a monoaminergic medication of the ergoline class which is used in the treatment of Parkinson's disease, migraine, and high prolactin levels.[1] It is taken by mouth.[1]

Side effects of lisuride include nausea and vomiting, dizziness, headache, fatigue or drowsiness, insomnia or sleep, gastrointestinal disturbances such as abdominal pain or diarrhea, nasal congestion or runny nose, and hypotension, hallucinations or confusion (particularly at higher doses). Rarely, serious side effects such as cardiac or pulmonary fibrosis have been reported with long-term use, but they are extremely uncommon.[2]

Lisuride acts as a mixed agonist and antagonist of dopamine, serotonin, and adrenergic receptors.[1][3][4][5] Activation of specific dopamine receptors is thought to be responsible for its effectiveness in the treatment of Parkinson's disease and ability to suppress prolactin levels,[1] while interactions with serotonin receptors are thought to be principally involved in its effectiveness for migraine.[6][7]

Medical uses

Lisuride is used to lower prolactin and, in low doses, to prevent migraine attacks.[1] The use of lisuride as initial antiparkinsonian medication for Parkinson's disease has been advocated, delaying the need for levodopa until 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 or bromocriptine.[8][9]

Side effects

Side effects of lisuride include nausea and lowered blood pressure, among others.[2]

Pharmacology

Pharmacodynamics

Lisuride is a ligand of dopamine, serotonin, and adrenergic receptors as well as the histamine H1 receptor.[3] It has sub-nanomolar affinity for the dopamine D2, and D3 receptors, serotonin 5-HT1A and 5-HT1D receptors, and α2A-, α2B-, and α2C-adrenergic receptors, and low-nanomolar affinity for the dopamine D1, D4, and D5 receptors, serotonin 5-HT2A, 5-HT2B, and 5-HT2C receptors, α1A-, α1B-, and α1D-adrenergic receptors, and histamine H1 receptor.[3][10][11] Lisuride is a partial agonist of the D2, D3, D4, 5-HT2A, 5-HT2C, 5-HT5A, and H1 receptors, a full or near-full agonist of the 5-HT1A, 5-HT1B, and 5-HT1D receptors, and a silent antagonist of the 5-HT2B receptor and α1A-, α2A-, α2B-, and α2C-adrenergic receptors.[4][5][11][12][13][14] Due to its highly non-selective pharmacological 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 D2 receptors.[1]

While lisuride has a similar receptor binding profile to the more well-known and chemically similar ergoline lysergic acid diethylamide (LSD; N,N-diethyllysergamide) and acts as a partial agonist of the serotonin 5-HT2A receptor likewise,[5] it lacks the psychedelic effects of LSD.[1] Research suggests that the lack of psychedelic effects with lisuride arises from biased agonism of the 5-HT2A receptor. Stimulation of the 5-HT2A protomer within the 5-HT2A–mGlu2 receptor complex evokes psychedelic effects, while these effects do not occur during sole stimulation of monomeric 5-HT2A receptors. Accordingly, different G proteins are involved.[15][16] Lisuride behaves as an agonist at the 5-HT2A receptor monomer. Since it competitively antagonizes the effects of LSD, it may be regarded as a protomer antagonist of the 5-HT2A–mGluR heteromer.[17] GPCR oligomers are discrete entities and usually possess properties distinct from their parent monomeric receptors.

Lisuride dose-dependently suppresses prolactin levels due to its dopaminergic activity.[1][18] As an antagonist of the 5-HT2B receptor, lisuride has no risk of cardiac valvulopathy in contrast to related ergolines like pergolide and cabergoline.[1]

Minute amounts of lisuride suppress the firing of dorsal raphe serotonergic neurons, presumably due to agonist activity at 5-HT1A receptors. [19] 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[3][4][5][13][20]
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[14] Partial agonist[14]
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).[3]

Pharmacokinetics

Absorption of lisuride from the gastrointestinal tract with oral administration is complete.[2] The absolute bioavailability of lisuride is 10 to 20% due to high first-pass metabolism.[2] The plasma protein binding of lisuride is 60 to 70%.[2] Peak levels of lisuride occur 60 to 80 minutes after ingestion with high variability between individuals.[2] The elimination half-life of lisuride is approximately 2 hours.[2] This is shorter than most other dopamine agonists.[2] Lisuride has more than 15 known metabolites.[2]

Chemistry

Lisuride is described as the free base and as the hydrogen maleate salt.[21][22][23]

Bromination of lisuride gives bromerguride (2-bromolisuride), which has a "reversed pharmacodynamic profile" compared to that of lisuride.[24]

History

Lisuride was synthesized by Zikán and Semonský at the Research Institute for Pharmacy and Biochemistry at Prague (later SPOFA) as an antimigraine agent analogous to methysergide and was described in 1960.[1][25] It was marketed by the early 1970s.[26]

Society and culture

Generic names

Lisuride is the INN and lysuride is the BAN.[21][27][22][23]

Brand names

Lisuride has been sold under brand names including Arolac, Cuvalit, Dopagon, Dopergin, Dopergine, Eunal, Lisenil, Lizenil, Lysenyl, Proclacam, Prolacam, and Revanil.[21][22][23][1]

Availability

Lisuride was previously more widely available throughout the world,[22][1] but as of 2020 it appears to be marketed only in Egypt, France , Italy, Kuwait, Lebanon, Mexico, New Zealand, and Pakistan .[23] Lisuride is not currently available in the United States , as the drug was not a commercial success.

Research

Preliminary clinical research suggests that transdermal administration of lisuride may be useful in the treatment of Parkinson'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 a transdermal patch and subcutaneous implant for the treatment of Parkinson's disease, restless legs syndrome, and dyskinesias in the 2000s and 2010s, but development was discontinued.[28][29]

References

  1. ↑ 1.00 1.01 1.02 1.03 1.04 1.05 1.06 1.07 1.08 1.09 1.10 1.11 1.12 1.13 1.14 1.15 1.16 1.17 "Classical dopamine agonists". Journal of Neural Transmission 126 (4): 449–454. April 2019. doi:10.1007/s00702-019-01989-y. PMID 30805732. 
  2. ↑ 2.00 2.01 2.02 2.03 2.04 2.05 2.06 2.07 2.08 2.09 2.10 2.11 2.12 "DA agonists -- ergot derivatives: lisuride: management of Parkinson's disease". Movement Disorders 17 Suppl 4 (S4): S74–S78. 2002. doi:10.1002/mds.5565. PMID 12211144. 
  3. ↑ 3.0 3.1 3.2 3.3 3.4 "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. November 2002. doi:10.1124/jpet.102.039867. PMID 12388666. 
  4. ↑ 4.0 4.1 4.2 "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. November 2002. doi:10.1124/jpet.102.039875. PMID 12388667. 
  5. ↑ 5.0 5.1 5.2 5.3 "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. November 2002. doi:10.1124/jpet.102.039883. PMID 12388668. 
  6. ↑ "Activation of 5-hydroxytryptamine1B/1D/1F receptors as a mechanism of action of antimigraine drugs". Expert Opinion on Pharmacotherapy 14 (12): 1599–1610. August 2013. doi:10.1517/14656566.2013.806487. PMID 23815106. 
  7. ↑ "The Role of 5-Hydroxytryptamine in the Pathophysiology of Migraine and its Relevance to the Design of Novel Treatments". Mini Reviews in Medicinal Chemistry 17 (11): 928–938. 2017. doi:10.2174/1389557516666160728121050. PMID 27465216. 
  8. ↑ "Lisuride for levodopa-induced complications in Parkinson's disease". The Cochrane Database of Systematic Reviews 1999 (2): CD001515. 2000. doi:10.1002/14651858.CD001515. PMID 10796801. 
  9. ↑ "Lisuride versus bromocriptine for levodopa-induced complications in Parkinson's disease". The Cochrane Database of Systematic Reviews 1999 (2): CD001514. 2000. doi:10.1002/14651858.CD001514. PMID 10796800. 
  10. ↑ "Re-evaluation of lisuride pharmacology: 5-hydroxytryptamine1A receptor-mediated behavioral effects overlap its other properties in rats". Psychopharmacology 164 (1): 93–107. October 2002. doi:10.1007/s00213-002-1141-z. PMID 12373423. 
  11. ↑ 11.0 11.1 "Agonist activity of LSD and lisuride at cloned 5HT2A and 5HT2C receptors". Psychopharmacology 136 (4): 409–414. April 1998. doi:10.1007/s002130050585. PMID 9600588. 
  12. ↑ "Lisuride, a dopamine receptor agonist with 5-HT2B receptor antagonist properties: absence of cardiac valvulopathy adverse drug reaction reports supports the concept of a crucial role for 5-HT2B receptor agonism in cardiac valvular fibrosis". Clinical Neuropharmacology 29 (2): 80–86. 2006. doi:10.1097/00002826-200603000-00005. PMID 16614540. 
  13. ↑ 13.0 13.1 "8R-lisuride is a potent stereospecific histamine H1-receptor partial agonist". Molecular Pharmacology 65 (3): 538–549. March 2004. doi:10.1124/mol.65.3.538. PMID 14978232. 
  14. ↑ 14.0 14.1 14.2 "Inactive and active state structures template selective tools for the human 5-HT5A receptor". Nature Structural & Molecular Biology 29 (7): 677–687. July 2022. doi:10.1038/s41594-022-00796-6. PMID 35835867. 
  15. ↑ "Metabotropic glutamate mGlu2 receptor is necessary for the pharmacological and behavioral effects induced by hallucinogenic 5-HT2A receptor agonists". Neuroscience Letters 493 (3): 76–79. April 2011. doi:10.1016/j.neulet.2011.01.046. PMID 21276828. 
  16. ↑ "Identification of a serotonin/glutamate receptor complex implicated in psychosis". Nature 452 (7183): 93–97. March 2008. doi:10.1038/nature06612. PMID 18297054. Bibcode: 2008Natur.452...93G. 
  17. ↑ "Hallucinogens recruit specific cortical 5-HT(2A) receptor-mediated signaling pathways to affect behavior". Neuron 53 (3): 439–452. February 2007. doi:10.1016/j.neuron.2007.01.008. PMID 17270739. 
  18. ↑ "Dopamine Agonists: From the 1970s to Today". Neuroendocrinology 109 (1): 34–41. 2019. doi:10.1159/000499470. PMID 30852578. 
  19. ↑ "Response of central monoaminergic neurons to lisuride: comparison with LSD". Life Sci. 24 (14): 1289–1297. 1979. doi:10.1016/0024-3205(79)90148-6. PMID 470543. 
  20. ↑ "PDSP Database - UNC". https://pdsp.unc.edu/databases/pdsp.php?testFreeRadio=testFreeRadio&testLigand=Lisuride&doQuery=Submit+Query. 
  21. ↑ 21.0 21.1 21.2 The Dictionary of Drugs: Chemical Data: Chemical Data, Structures and Bibliographies. Springer. 14 November 2014. pp. 747–. ISBN 978-1-4757-2085-3. https://books.google.com/books?id=0vXTBwAAQBAJ&pg=PA747. 
  22. ↑ 22.0 22.1 22.2 22.3 Index Nominum 2000: International Drug Directory. Taylor & Francis. 2000. pp. 612–. ISBN 978-3-88763-075-1. https://books.google.com/books?id=5GpcTQD_L2oC&pg=PA612. 
  23. ↑ 23.0 23.1 23.2 23.3 "Dopergin". https://www.drugs.com/international/lisuride.html. 
  24. ↑ "Pharmacokinetics of bromerguride, a new dopamine-antagonistic ergot derivative in rat and dog". European Journal of Drug Metabolism and Pharmacokinetics 12 (1): 31–40. January 1987. doi:10.1007/BF03189859. PMID 3609071. 
  25. ↑ "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. 1960. doi:10.1135/cccc19601922. ISSN 0010-0765. 
  26. ↑ "General Anesthetics". Pharmacology and Pharmacotherapeutics. Popular Prakashan. 1973. pp. 929–. ISBN 978-81-7991-527-1. https://books.google.com/books?id=7d493VOD4P8C&pg=PA929. 
  27. ↑ Concise Dictionary of Pharmacological Agents: Properties and Synonyms. Springer Science & Business Media. 31 October 1999. pp. 170–. ISBN 978-0-7514-0499-9. https://books.google.com/books?id=mqaOMOtk61IC&pg=PA170. 
  28. ↑ "Lisuride - Axxonis Pharma". AdisInsight. Springer Nature Switzerland AG. https://adisinsight.springer.com/drugs/800024391. 
  29. ↑ "Lisuride implant - Titan Pharmaceuticals". AdisInsight. Springer Nature Switzerland AG. https://adisinsight.springer.com/drugs/800027415. 



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