Lisuride

Lisuride
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
  • 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
IUPAC name
  • 1,1-Diethyl-3-(7-methyl-4,6,6a,7,8,9-hexahydro-indolo[4,3-fg]quinolin-9-yl)-urea
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard100.038.099
Edit this at Wikidata
Chemical and physical data
FormulaC20H26N4O
Molar mass338.455 g·mol−1
3D model (JSmol)
SMILES
  • [H][C@@]12Cc3c[nH]c4cccc(C1=C[C@H](NC(=O)N(CC)CC)CN2C)c34
InChI
  • 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/s1 checkY
  • Key:BKRGVLQUQGGVSM-KBXCAEBGSA-N checkY
  (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 decreased blood pressure, among others.[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] 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, 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] 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 amide (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.[14][15] 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.[16] 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][17] 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]

Activities of lisuride at various sites[3][4][5][13][18]
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
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.[19][20][21]

Bromination of lisuride gives bromerguride (2-bromolisuride), which has a "reversed pharmacodynamic profile" compared to that of lisuride.[22]

History

Lysergide 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][23] It was marketed by the early 1970s.[24]

Society and culture

Generic names

Lisuride is the INN and lysuride is the BAN.[19][25][20][21]

Brand names

Lisuride has been sold under brand names including Arolac, Cuvalit, Dopagon, Dopergin, Dopergine, Eunal, Lisenil, Lizenil, Lysenyl, Proclacam, Prolacam, and Revanil.[19][20][21][1]

Availability

Lisuride was previously more widely available throughout the world,[20][1] but as of 2020 it appears to be marketed only in Egypt, France, Italy, Kuwait, Lebanon, Mexico, New Zealand, and Pakistan.[21] Lisuride is not currently available in the United States, as the drug was not a commercial success in comparison with other dopamine receptor agonists.

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.[26][27]

References

  1. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 Horowski R, Löschmann PA (April 2019). "Classical dopamine agonists". J Neural Transm (Vienna). 126 (4): 449–454. doi:10.1007/s00702-019-01989-y. PMID 30805732. S2CID 71144049.
  2. 1 2 3 4 5 6 7 8 9 10 11 12 13 "DA agonists - Ergot derivaties: Lisuride". Movement Disorders. 17 (S4): S74–S78. 2002. doi:10.1002/mds.5565. ISSN 0885-3185. PMID 12211144. S2CID 79230929.
  3. 1 2 3 4 5 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". J Pharmacol Exp Ther. 303 (2): 791–804. doi:10.1124/jpet.102.039867. PMID 12388666. S2CID 6200455.
  4. 1 2 3 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". J Pharmacol Exp Ther. 303 (2): 805–14. doi:10.1124/jpet.102.039875. PMID 12388667. S2CID 35238120.
  5. 1 2 3 4 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". J Pharmacol Exp Ther. 303 (2): 815–22. doi:10.1124/jpet.102.039883. PMID 12388668. S2CID 19260572.
  6. ↑ Ramírez Rosas MB, Labruijere S, Villalón CM, Maassen Vandenbrink A (August 2013). "Activation of 5-hydroxytryptamine1B/1D/1F receptors as a mechanism of action of antimigraine drugs". Expert Opin Pharmacother. 14 (12): 1599–610. doi:10.1517/14656566.2013.806487. PMID 23815106. S2CID 22721405.
  7. ↑ Villalón CM, VanDenBrink AM (2017). "The Role of 5-Hydroxytryptamine in the Pathophysiology of Migraine and its Relevance to the Design of Novel Treatments". Mini Rev Med Chem. 17 (11): 928–938. doi:10.2174/1389557516666160728121050. PMID 27465216.
  8. ↑ Clarke CE, Speller JM (2000). "Lisuride for levodopa-induced complications in Parkinson's disease". Cochrane Database Syst Rev (2): CD001515. doi:10.1002/14651858.CD001515. PMC 7025784. PMID 10796801.
  9. ↑ Clarke CE, Speller JM (2000). "Lisuride versus bromocriptine for levodopa-induced complications in Parkinson's disease". Cochrane Database Syst Rev (2): CD001514. doi:10.1002/14651858.CD001514. PMC 7028005. PMID 10796800.
  10. ↑ Marona-Lewicka D, Kurrasch-Orbaugh DM, Selken JR, Cumbay MG, Lisnicchia JG, Nichols DE (October 2002). "Re-evaluation of lisuride pharmacology: 5-hydroxytryptamine1A receptor-mediated behavioral effects overlap its other properties in rats". Psychopharmacology. 164 (1): 93–107. doi:10.1007/s00213-002-1141-z. PMID 12373423. S2CID 19825878.
  11. 1 2 Egan CT, Herrick-Davis K, Miller K, Glennon RA, Teitler M (April 1998). "Agonist activity of LSD and lisuride at cloned 5HT2A and 5HT2C receptors". Psychopharmacology. 136 (4): 409–14. doi:10.1007/s002130050585. PMID 9600588. S2CID 3021798.
  12. ↑ Hofmann C, Penner U, Dorow R, Pertz HH, Jähnichen S, Horowski R, Latté KP, Palla D, Schurad B (2006). "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". Clin Neuropharmacol. 29 (2): 80–6. doi:10.1097/00002826-200603000-00005. PMID 16614540. S2CID 33849447.
  13. 1 2 Bakker RA, Weiner DM, ter Laak T, Beuming T, Zuiderveld OP, Edelbroek M, Hacksell U, Timmerman H, Brann MR, Leurs R (March 2004). "8R-lisuride is a potent stereospecific histamine H1-receptor partial agonist". Mol Pharmacol. 65 (3): 538–49. doi:10.1124/mol.65.3.538. PMID 14978232.
  14. ↑ Moreno JL, Holloway T, Albizu L, Sealfon SC, González-Maeso J (2011). "Metabotropic glutamate mGlu2 receptor is necessary for the pharmacological and behavioral effects induced by hallucinogenic 5-HT2A receptor agonists". Neurosci. Lett. 493 (3): 76–9. doi:10.1016/j.neulet.2011.01.046. PMC 3064746. PMID 21276828.
  15. ↑ González-Maeso J, Ang RL, Yuen T, et al. (2008). "Identification of a serotonin/glutamate receptor complex implicated in psychosis". Nature. 452 (7183): 93–7. Bibcode:2008Natur.452...93G. doi:10.1038/nature06612. PMC 2743172. PMID 18297054.
  16. ↑ González-Maeso J, et al. (2007). "Hallucinogens recruit specific cortical 5-HT(2A) receptor-mediated signaling pathways to affect behavior". Neuron. 53 (3): 439–52. doi:10.1016/j.neuron.2007.01.008. PMID 17270739. S2CID 16309730.
  17. ↑ Auriemma RS, Pirchio R, De Alcubierre D, Pivonello R, Colao A (2019). "Dopamine Agonists: From the 1970s to Today". Neuroendocrinology. 109 (1): 34–41. doi:10.1159/000499470. PMID 30852578.
  18. ↑ "Archived copy". pdsp.unc.edu. Archived from the original on 13 April 2021. Retrieved 15 January 2022.{{cite web}}: CS1 maint: archived copy as title (link)
  19. 1 2 3 J. Elks (14 November 2014). The Dictionary of Drugs: Chemical Data: Chemical Data, Structures and Bibliographies. Springer. pp. 747–. ISBN 978-1-4757-2085-3.
  20. 1 2 3 4 Index Nominum 2000: International Drug Directory. Taylor & Francis. 2000. pp. 612–. ISBN 978-3-88763-075-1.
  21. 1 2 3 4 "Dopergin". Archived from the original on 2020-11-27.
  22. ↑ Hildebrand, M.; Hümpel, M.; Krause, W.; Täuber, U. (January 1987). "Pharmacokinetics of bromerguride, a new dopamineantagonistic ergot derivative in rat and dog". European Journal of Drug Metabolism and Pharmacokinetics. 12 (1): 31–40. doi:10.1007/BF03189859. PMID 3609071. S2CID 22838914.
  23. ↑ 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. ISSN 0010-0765.
  24. ↑ R. S. Satoskar; S. D. Bhandarkar &nirmala N. Rege (1973). Pharmacology and Pharmacotherapeutics. Popular Prakashan. pp. 929–. ISBN 978-81-7991-527-1.
  25. ↑ I.K. Morton; Judith M. Hall (31 October 1999). Concise Dictionary of Pharmacological Agents: Properties and Synonyms. Springer Science & Business Media. pp. 170–. ISBN 978-0-7514-0499-9.
  26. ↑ "Lisuride - axxonis - AdisInsight".
  27. ↑ "Research programme: CNS therapeutics - Titan Pharmaceuticals - AdisInsight".
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