Lisuride Explained

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.

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.

Lisuride acts as a mixed agonist and antagonist of dopamine, serotonin, and adrenergic receptors. 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, while interactions with serotonin receptors are thought to be principally involved in its effectiveness for migraine.[2] [3]

Medical uses

Lisuride is used to lower prolactin and, in low doses, to prevent migraine attacks. 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. Evidence is insufficient to support lisuride in the treatment of advanced Parkinson's disease as an alternative to levodopa or bromocriptine.[4] [5]

Side effects

Side effects of lisuride include nausea and lowered blood pressure, among others.[6]

Pharmacology

Pharmacodynamics

Lisuride is a ligand of dopamine, serotonin, and adrenergic receptors as well as the histamine H1 receptor.[7] 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.[8] [9] 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.[10] [11] [12] [13] [14] Due to its highly non-selective pharmacological activity, lisuride is described as a "dirty drug". The effectiveness of lisuride in Parkinson's disease and hyperprolactinemia is thought to be mostly due to activation of dopamine D2 receptors.

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, it lacks the psychedelic effects of LSD. 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.[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.

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.

! Site! Affinity (Ki [nM])! Efficacy (Emax [%])! Action
D165??
D2S0.3455Partial agonist
D2L0.6621Partial agonist
D30.2849Partial agonist
D44.632Partial agonist
D53.5??
5-HT1A0.1598Full agonist
5-HT1B1985Partial agonist
5-HT1D0.9881Partial agonist
5-HT2A2.852Partial agonist
5-HT2B1.30Silent antagonist
5-HT2C6.675Partial agonist
5-HT5A?11Partial agonist
α1A5.50Silent antagonist
α1B17??
α1D3.0??
α2A0.0550Silent antagonist
α2B0.130Silent antagonist
α2C0.130Silent antagonist
α2D0.79??
β168??
β27.9??
H135?Partial agonist
M1>10,000––
Notes: All receptors are human except α2D-adrenergic, which is rat (no human counterpart).

Pharmacokinetics

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

Chemistry

Lisuride is described as the free base and as the hydrogen maleate salt.

Bromination of lisuride gives bromerguride (2-bromolisuride), which has a "reversed pharmacodynamic profile" compared to that of lisuride.[20]

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.[21] It was marketed by the early 1970s.[22]

Society and culture

Generic names

Lisuride is the and lysuride is the .[23] [24] [25] [26]

Brand names

Lisuride has been sold under brand names including Arolac, Cuvalit, Dopagon, Dopergin, Dopergine, Eunal, Lisenil, Lizenil, Lysenyl, Proclacam, Prolacam, and Revanil.

Availability

Lisuride was previously more widely available throughout the world, but as of 2020 it appears to be marketed only in Egypt, France, Italy, Kuwait, Lebanon, Mexico, New Zealand, and Pakistan. 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. 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. 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.[27] [28]

Notes and References

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  2. Ramírez Rosas MB, Labruijere S, Villalón CM, Maassen Vandenbrink A . 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 . 23815106 . 10.1517/14656566.2013.806487 . 22721405 .
  3. Villalón CM, VanDenBrink AM . 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 . 27465216 . 10.2174/1389557516666160728121050 .
  4. Clarke CE, Speller JM . Lisuride for levodopa-induced complications in Parkinson's disease . The Cochrane Database of Systematic Reviews . 1999. 2 . CD001515 . 2000 . 10796801 . 7025784 . 10.1002/14651858.CD001515 .
  5. Clarke CE, Speller JM . Lisuride versus bromocriptine for levodopa-induced complications in Parkinson's disease . The Cochrane Database of Systematic Reviews . 1999. 2 . CD001514 . 2000 . 10796800 . 7028005 . 10.1002/14651858.CD001514 .
  6. DA agonists -- ergot derivatives: lisuride: management of Parkinson's disease . Movement Disorders . 17 Suppl 4 . S4 . S74–S78 . 2002 . 12211144 . 10.1002/mds.5565 . 79230929 .
  7. Millan MJ, Maiofiss L, Cussac D, Audinot V, Boutin JA, Newman-Tancredi A . 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 . 12388666 . 10.1124/jpet.102.039867 . 6200455 .
  8. Marona-Lewicka D, Kurrasch-Orbaugh DM, Selken JR, Cumbay MG, Lisnicchia JG, Nichols DE . Re-evaluation of lisuride pharmacology: 5-hydroxytryptamine1A receptor-mediated behavioral effects overlap its other properties in rats . Psychopharmacology . 164 . 1 . 93–107 . October 2002 . 12373423 . 10.1007/s00213-002-1141-z . 19825878 .
  9. Egan CT, Herrick-Davis K, Miller K, Glennon RA, Teitler M . Agonist activity of LSD and lisuride at cloned 5HT2A and 5HT2C receptors . Psychopharmacology . 136 . 4 . 409–414 . April 1998 . 9600588 . 10.1007/s002130050585 . 3021798 .
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  13. Bakker RA, Weiner DM, ter Laak T, Beuming T, Zuiderveld OP, Edelbroek M, Hacksell U, Timmerman H, Brann MR, Leurs R . 6 . 8R-lisuride is a potent stereospecific histamine H1-receptor partial agonist . Molecular Pharmacology . 65 . 3 . 538–549 . March 2004 . 14978232 . 10.1124/mol.65.3.538 . 19140579 .
  14. Zhang S, Chen H, Zhang C, Yang Y, Popov P, Liu J, Krumm BE, Cao C, Kim K, Xiong Y, Katritch V, Shoichet BK, Jin J, Fay JF, Roth BL . 6 . Inactive and active state structures template selective tools for the human 5-HT5A receptor . Nature Structural & Molecular Biology . 29 . 7 . 677–687 . July 2022 . 35835867 . 9299520 . 10.1038/s41594-022-00796-6 .
  15. Moreno JL, Holloway T, Albizu L, Sealfon SC, González-Maeso J . 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 . 21276828 . 3064746 . 10.1016/j.neulet.2011.01.046 .
  16. González-Maeso J, Ang RL, Yuen T, Chan P, Weisstaub NV, López-Giménez JF, Zhou M, Okawa Y, Callado LF, Milligan G, Gingrich JA, Filizola M, Meana JJ, Sealfon SC . 6 . Identification of a serotonin/glutamate receptor complex implicated in psychosis . Nature . 452 . 7183 . 93–97 . March 2008 . 18297054 . 2743172 . 10.1038/nature06612 . 2008Natur.452...93G .
  17. González-Maeso J, Weisstaub NV, Zhou M, Chan P, Ivic L, Ang R, Lira A, Bradley-Moore M, Ge Y, Zhou Q, Sealfon SC, Gingrich JA . 6 . Hallucinogens recruit specific cortical 5-HT(2A) receptor-mediated signaling pathways to affect behavior . Neuron . 53 . 3 . 439–452 . February 2007 . 17270739 . 10.1016/j.neuron.2007.01.008 . 16309730 . free .
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  20. Hilderbrand M, Hümpel M, Krause W, Täuber U . 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 . 3609071 . 10.1007/BF03189859 . 22838914 .
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  26. Web site: Dopergin. https://web.archive.org/web/20201127010433/https://www.drugs.com/international/lisuride.html. 2020-11-27.
  27. Web site: Lisuride - Axxonis Pharma . AdisInsight . Springer Nature Switzerland AG .
  28. Web site: Lisuride implant - Titan Pharmaceuticals . AdisInsight . Springer Nature Switzerland AG .

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