![]() | |
Clinical data | |
---|---|
Trade names | Dopergin, others |
Other names | Lysuride; Mesorgydin; Methylergol carbamide |
AHFS/Drugs.com | International Drug Names |
Routes of administration | Oral [1] Investigational: Subcutaneous implant, transdermal patch [1] |
ATC code | |
Legal status | |
Legal status | |
Pharmacokinetic data | |
Bioavailability | 10–20% [3] |
Protein binding | 60–70% [3] |
Metabolism | Hepatic |
Metabolites | More than 15 known [3] |
Elimination half-life | 2 hours [3] |
Excretion | Renal and biliary in equal amounts |
Identifiers | |
| |
CAS Number | |
PubChem CID | |
IUPHAR/BPS | |
DrugBank | |
ChemSpider | |
UNII | |
KEGG | |
ChEBI | |
ChEMBL | |
CompTox Dashboard (EPA) | |
ECHA InfoCard | 100.038.099 |
Chemical and physical data | |
Formula | C20H26N4O |
Molar mass | 338.455 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. [3]
Lisuride acts as a mixed agonist and antagonist of dopamine, 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]
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. [9] [10]
Side effects of lisuride include nausea and lowered blood pressure, among others. [3]
Lisuride is a ligand of dopamine, serotonin, and adrenergic receptors as well as the histamine H1 receptor. [4] 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. [4] [11] [12] 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. [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 lysergic acid diethylamide (LSD; N,N-diethyllysergamide) and acts as a partial agonist of the serotonin 5-HT2A receptor likewise, [6] it lacks the psychedelic effects of LSD and hence is non-hallucinogenic. [16] [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. [17] [18] 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. [19] GPCR oligomers are 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–mGlu2 dimers may not be essential for psychedelic effects. [20] [21] Lisuride shows weak or no Gq pathway recruitment and this may be responsible for its non-hallucinogenic nature. [22] [23]
Lisuride dose-dependently suppresses prolactin levels due to its dopaminergic activity. [1] [24] 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. [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.
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] |
Absorption of lisuride from the gastrointestinal tract with oral administration is complete. [3] The absolute bioavailability of lisuride is 10 to 20% due to high first-pass metabolism. [3] The plasma protein binding of lisuride is 60 to 70%. [3] Peak levels of lisuride occur 60 to 80 minutes after ingestion with high variability between individuals. [3] The 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]
Lisuride is described as the free base and as the hydrogen maleate salt. [27] [28] [29]
Bromination of lisuride gives bromerguride (2-bromolisuride), which has a "reversed pharmacodynamic profile" compared to that of lisuride. [30]
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] [31] It was marketed by the early 1970s. [32]
Lisuride is the INN and lysuride is the BAN . [27] [33] [28] [29]
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]
Lisuride was previously more widely available throughout the world, [28] [1] but as of 2020 it appears to be marketed only in Egypt, France, Italy, Kuwait, Lebanon, Mexico, New Zealand, and Pakistan. [29] Lisuride is not currently available in the United States, as the drug was not a commercial success.
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. [34] [35]
Psychedelics are a subclass of hallucinogenic drugs whose primary effect is to trigger non-ordinary mental states and a perceived "expansion of consciousness". Also referred to as classic hallucinogens or serotonergic hallucinogens, the term psychedelic is sometimes used more broadly to include various types of hallucinogens, such as those which are atypical or adjacent to psychedelia like salvia and MDMA, respectively.
Ergotamine, sold under the brand name Ergomar among others, is an ergopeptine and part of the ergot family of alkaloids; it is structurally and biochemically closely related to ergoline. It is structurally similar to several neurotransmitters, and it acts as a vasoconstrictor. It is used for acute migraines, sometimes with caffeine as the combination ergotamine/caffeine.
Bromocriptine, originally marketed as Parlodel and subsequently under many brand names, is an ergoline derivative and dopamine agonist that is used in the treatment of pituitary tumors, Parkinson's disease, hyperprolactinaemia, neuroleptic malignant syndrome, and, as an adjunct, type 2 diabetes.
Pergolide, sold under the brand name Permax and Prascend (veterinary) among others, is an ergoline-based dopamine receptor agonist used in some countries for the treatment of Parkinson's disease. Parkinson's disease is associated with reduced dopamine synthesis in the substantia nigra of the brain. Pergolide acts on many of the same receptors as dopamine to increase receptor activity.
Cabergoline, sold under the brand name Dostinex among others, is a dopaminergic medication used in the treatment of high prolactin levels, prolactinomas, Parkinson's disease, and for other indications. It is taken by mouth.
Dopaminergic means "related to dopamine", a common neurotransmitter. Dopaminergic substances or actions increase dopamine-related activity in the brain.
Methylergometrine, also known as methylergonovine and sold under the brand name Methergine, is a medication of the ergoline and lysergamide groups which is used as an oxytocic in obstetrics and as an antimigraine agent in the treatment of migraine headaches. It reportedly produces psychedelic effects similar to those of lysergic acid diethylamide (LSD) at high doses.
Methysergide, sold under the brand names Deseril and Sansert, is a monoaminergic medication of the ergoline and lysergamide groups which is used in the prophylaxis and treatment of migraine and cluster headaches. It has been withdrawn from the market in the United States and Canada due to safety concerns. It is taken by mouth.
A dopamine agonist is a compound that activates dopamine receptors. There are two families of dopamine receptors, D1-like and D2-like. They are all G protein-coupled receptors. D1- and D5-receptors belong to the D1-like family and the D2-like family includes D2, D3 and D4 receptors. Dopamine agonists are primarily used in the treatment of the motor symptoms of Parkinson's disease, and to a lesser extent, in hyperprolactinemia and restless legs syndrome. They are also used off-label in the treatment of clinical depression. Impulse control disorders are associated with the use of dopamine agonists for whatever condition.
The 5-HT2A receptor is a subtype of the 5-HT2 receptor that belongs to the serotonin receptor family and is a G protein-coupled receptor (GPCR). The 5-HT2A receptor is a cell surface receptor, but has several intracellular locations.
Cardiac fibrosis commonly refers to the excess deposition of extracellular matrix in the cardiac muscle, but the term may also refer to an abnormal thickening of the heart valves due to inappropriate proliferation of cardiac fibroblasts. Fibrotic cardiac muscle is stiffer and less compliant and is seen in the progression to heart failure. The description below focuses on a specific mechanism of valvular pathology but there are other causes of valve pathology and fibrosis of the cardiac muscle.
Mesulergine (INNTooltip International Nonproprietary Name) (developmental code name CU-32085) is a drug of the ergoline group which was never marketed. It acts on serotonin and dopamine receptors. Specifically, it is an agonist of dopamine D2-like receptors and serotonin 5-HT6 receptors and an antagonist of serotonin 5-HT2A, 5-HT2B, 5-HT2C, and 5-HT7 receptors.. It also has affinity for the 5-HT1A, 5-HT1B, 5-HT1D, 5-HT1F, and 5-HT5A receptors. The compound had entered clinical trials for the treatment of Parkinson's disease; however, further development was halted due to adverse histological abnormalities in rats. It was also investigated for the treatment of hyperprolactinemia (high prolactin levels).
5-Hydroxytryptamine receptor 2B (5-HT2B) also known as serotonin receptor 2B is a protein that in humans is encoded by the HTR2B gene. 5-HT2B is a member of the 5-HT2 receptor family that binds the neurotransmitter serotonin (5-hydroxytryptamine, 5-HT). Like all 5-HT2 receptors, the 5-HT2B receptor is Gq/G11-protein coupled, leading to downstream activation of phospholipase C.
Terguride, sold under the brand name Teluron, is a serotonin receptor antagonist and dopamine receptor agonist of the ergoline family. It is approved for and used as a prolactin inhibitor in the treatment of hyperprolactinemia in Japan. Terguride is taken by mouth.
Pimavanserin, sold under the brand name Nuplazid, is an atypical antipsychotic which is approved for the treatment of Parkinson's disease psychosis. It is taken by mouth.
Serotonin antagonist and reuptake inhibitors (SARIs) are a class of drugs used mainly as antidepressants, but also as anxiolytics and hypnotics. They act by antagonizing serotonin receptors such as 5-HT2A and inhibiting the reuptake of serotonin, norepinephrine, and/or dopamine. Additionally, most also antagonize α1-adrenergic receptors. The majority of the currently marketed SARIs belong to the phenylpiperazine class of compounds.
S32212 is a drug which is under preclinical investigation as a potential antidepressant medicine. It behaves as a selective, combined 5-HT2C receptor inverse agonist and α2-adrenergic receptor antagonist (at all three subtypes—α2A, α2B, and α2C) with additional 5-HT2A and, to a lesser extent, 5-HT2B receptor antagonistic properties, and lacks any apparent affinity for the monoamine reuptake transporters or for the α1-adrenergic, H1, or mACh receptors. This profile of activity is compatible with the definition of a noradrenergic and specific serotonergic antidepressant (NaSSA), and as such, S32212 could in turn be classified as a NaSSA.
The head-twitch response (HTR), also sometimes known as wet dog shakes (WDS) in rats, is a rapid side-to-side head movement that occurs in mice and rats when the serotonin 5-HT2A receptor is activated. Serotonergic psychedelics like lysergic acid diethylamide (LSD) and psilocybin consistently induce the HTR in rodents. Because of this, the HTR is widely employed in scientific research as an animal behavioral model of hallucinogen effects and in the discovery of new psychedelic drugs.
Peripherally selective drugs have their primary mechanism of action outside of the central nervous system (CNS), usually because they are excluded from the CNS by the blood–brain barrier. By being excluded from the CNS, drugs may act on the rest of the body without producing side-effects related to their effects on the brain or spinal cord. For example, most opioids cause sedation when given at a sufficiently high dose, but peripherally selective opioids can act on the rest of the body without entering the brain and are less likely to cause sedation. These peripherally selective opioids can be used as antidiarrheals, for instance loperamide (Imodium).
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].
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)].