Lisuride

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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
  • BR: Class C1 (Other controlled substances)[2]
  • In general: ℞ (Prescription only)
Pharmacokinetic data
Bioavailability10–20%[3]
Protein binding60–70%[3]
MetabolismHepatic
MetabolitesMore than 15 known[3]
Elimination half-life2 hours[3]
ExcretionRenal and biliary in equal amounts
Identifiers
  • 1,1-Diethyl-3-(7-methyl-4,6,6a,7,8,9-hexahydro-indolo[4,3-fg]quinolin-9-yl)-urea
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/s1 checkY
  • Key:BKRGVLQUQGGVSM-KBXCAEBGSA-N checkY
  (verify)

Lisuride, sold under the brand name Dopergin among others, is a

high prolactin levels.[1] It is taken by mouth.[1]

Side effects of lisuride include nausea and vomiting, dizziness, headache,

drowsiness
, insomnia or sleep, gastrointestinal disturbances such as abdominal pain or diarrhea, nasal congestion or runny nose, and
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.[3]

Lisuride acts as a mixed

serotonin, and adrenergic 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 suppress prolactin levels,[1] while interactions with serotonin receptors are thought to be principally involved in its effectiveness for migraine.[7][8]

Medical uses

Lisuride is used to lower

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.[9][10]

Side effects

Side effects of lisuride include nausea and lowered blood pressure, among others.[3]

Pharmacology

Pharmacodynamics

Lisuride is a

silent antagonist of the 5-HT2B receptor and α1A-, α2A-, α2B-, and α2C-adrenergic receptors.[5][6][12][13][14][15] 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

competitively antagonizes the effects of LSD, it may be regarded as a protomer antagonist of the 5-HT2A–mGluR heteromer.[18] GPCR oligomers
are discrete entities and usually possess properties distinct from their parent monomeric receptors.

Lisuride dose-dependently suppresses

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. [20] 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][21]
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

elimination half-life of lisuride is approximately 2 hours.[3] This is shorter than most other dopamine agonists.[3] Lisuride has more than 15 known metabolites.[3]

Chemistry

Lisuride is described as the

maleate salt.[22][23][24]

Bromination of lisuride gives bromerguride (2-bromolisuride), which has a "reversed pharmacodynamic profile" compared to that of lisuride.[25]

History

Lisuride was

antimigraine agent analogous to methysergide and was described in 1960.[1][26] It was marketed by the early 1970s.[27]

Society and culture

Generic names

Lisuride is the

INNTooltip International Nonproprietary Name and lysuride is the BANTooltip British Approved Name.[22][28][23][24]

Brand names

Lisuride has been sold under brand names including Arolac, Cuvalit, Dopagon, Dopergin, Dopergine, Eunal, Lisenil, Lizenil, Lysenyl, Proclacam, Prolacam, and Revanil.[22][23][24][1]

Availability

Lisuride was previously more widely available throughout the world,[23][1] but as of 2020 it appears to be marketed only in Egypt, France, Italy, Kuwait, Lebanon, Mexico, New Zealand, and Pakistan.[24] 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.[29][30]

References

  1. ^
    S2CID 71144049
    .
  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). Archived from the original on 2023-08-03. Retrieved 2023-08-16.
  3. ^
    S2CID 79230929
    .
  4. ^
    S2CID 6200455
    .
  5. ^
    S2CID 35238120
    .
  6. ^
    S2CID 19260572
    .
  7. S2CID 22721405
    .
  8. PMID 27465216
    .
  9. PMID 10796801
    .
  10. PMID 10796800
    .
  11. S2CID 19825878
    .
  12. ^
    S2CID 3021798
    .
  13. S2CID 33849447
    .
  14. ^
    S2CID 19140579
    .
  15. ^
    PMID 35835867
    .
  16. PMID 21276828
    .
  17. PMID 18297054
    .
  18. S2CID 16309730
    .
  19. PMID 30852578
    .
  20. PMID 470543
    .
  21. ^ "PDSP Database - UNC". pdsp.unc.edu. Archived from the original on 13 April 2021. Retrieved 15 January 2022.
  22. ^
    ISBN 978-1-4757-2085-3
    .
  23. ^
    ISBN 978-3-88763-075-1
    .
  24. ^ a b c d "Dopergin". Archived from the original on 2020-11-27.
  25. S2CID 22838914
    .
  26. ISSN 0010-0765
    .
  27. ISBN 978-81-7991-527-1
    .
  28. ISBN 978-0-7514-0499-9
    .
  29. ^ "Lisuride - Axxonis Pharma". AdisInsight. Springer Nature Switzerland AG.
  30. ^ "Lisuride implant - Titan Pharmaceuticals". AdisInsight. Springer Nature Switzerland AG.