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

monoaminergic Monoaminergic means "working on monoamine neurotransmitters", which include serotonin, dopamine, norepinephrine, epinephrine, and histamine. A monoaminergic, or monoaminergic drug, is a chemical, which functions to directly modulate the seroton ...

medication Medication (also called medicament, medicine, pharmaceutical drug, medicinal product, medicinal drug or simply drug) is a drug used to medical diagnosis, diagnose, cure, treat, or preventive medicine, prevent disease. Drug therapy (pharmaco ...

of the

ergoline Ergoline is a core structure in many alkaloids and their synthetic derivatives. Ergoline alkaloids were first characterized in ergot. Some of these are implicated in the condition of ergotism, which can take a convulsive form or a gangrenous for ...

family which is used in the treatment of

Parkinson's disease Parkinson's disease (PD), or simply Parkinson's, is a neurodegenerative disease primarily of the central nervous system, affecting both motor system, motor and non-motor systems. Symptoms typically develop gradually and non-motor issues become ...

migraine Migraine (, ) is a complex neurological disorder characterized by episodes of moderate-to-severe headache, most often unilateral and generally associated with nausea, and light and sound sensitivity. Other characterizing symptoms may includ ...

, and high prolactin levels. It is taken

by mouth Oral administration is a route of administration whereby a substance is taken through the Human mouth, mouth, swallowed, and then processed via the digestive system. This is a common route of administration for many medications. Oral administ ...

Side effect In medicine, a side effect is an effect of the use of a medicinal drug or other treatment, usually adverse but sometimes beneficial, that is unintended. Herbal and traditional medicines also have side effects. A drug or procedure usually use ...

s of lisuride include

nausea Nausea is a diffuse sensation of unease and discomfort, sometimes perceived as an urge to vomit. It can be a debilitating symptom if prolonged and has been described as placing discomfort on the chest, abdomen, or back of the throat. Over 30 d ...

and vomiting,

dizziness Dizziness is an imprecise term that can refer to a sense of disorientation in space, vertigo, or lightheadedness. It can also refer to Balance disorder, disequilibrium or a non-specific feeling, such as giddiness or foolishness. Dizziness is a ...

headache A headache, also known as cephalalgia, is the symptom of pain in the face, head, or neck. It can occur as a migraine, tension-type headache, or cluster headache. There is an increased risk of Depression (mood), depression in those with severe ...

fatigue Fatigue is a state of tiredness (which is not sleepiness), exhaustion or loss of energy. It is a signs and symptoms, symptom of any of various diseases; it is not a disease in itself. Fatigue (in the medical sense) is sometimes associated wit ...

drowsiness Somnolence (alternatively sleepiness or drowsiness) is a state of strong desire for sleep, or sleeping for unusually long periods (compare hypersomnia). It has distinct meanings and causes. It can refer to the usual state preceding falling asleep ...

insomnia Insomnia, also known as sleeplessness, is a sleep disorder where people have difficulty sleeping. They may have difficulty falling asleep, or staying asleep for as long as desired. Insomnia is typically followed by daytime sleepiness, low ene ...

or sleep, gastrointestinal disturbances such as

abdominal pain Abdominal pain, also known as a stomach ache, is a symptom associated with both non-serious and serious medical issues. Since the abdomen contains most of the body's vital organs, it can be an indicator of a wide variety of diseases. Given th ...

diarrhea Diarrhea (American English), also spelled diarrhoea or diarrhœa (British English), is the condition of having at least three loose, liquid, or watery bowel movements in a day. It often lasts for a few days and can result in dehydration d ...

, nasal congestion or runny nose, and

hypotension Hypotension, also known as low blood pressure, is a cardiovascular condition characterized by abnormally reduced blood pressure. Blood pressure is the force of blood pushing against the walls of the arteries as the heart pumps out blood and is ...

, and

hallucinations A hallucination is a perception in the absence of an external stimulus that has the compelling sense of reality. They are distinguishable from several related phenomena, such as dreaming ( REM sleep), which does not involve wakefulness; pse ...

confusion In psychology, confusion is the quality or emotional state of being bewildered or unclear. The term "acute mental confusion"

(particularly at higher doses). Rarely, serious side effects such as

cardiac The heart is a muscular organ found in humans and other animals. This organ pumps blood through the blood vessels. The heart and blood vessels together make the circulatory system. The pumped blood carries oxygen and nutrients to the tissu ...

pulmonary fibrosis Pulmonary fibrosis is a condition in which the lungs become scarred over time. Symptoms include shortness of breath, a dry cough, feeling tired, weight loss, and nail clubbing. Complications may include pulmonary hypertension, respiratory ...

have been reported with long-term use, but they are extremely uncommon. Lisuride acts as a mixed

agonist An agonist is a chemical that activates a Receptor (biochemistry), receptor to produce a biological response. Receptors are Cell (biology), cellular proteins whose activation causes the cell to modify what it is currently doing. In contrast, an R ...

and

antagonist An antagonist is a character in a story who is presented as the main enemy or rival of the protagonist and is often depicted as a villain.dopamine Dopamine (DA, a contraction of 3,4-dihydroxyphenethylamine) is a neuromodulatory molecule that plays several important roles in cells. It is an organic chemical of the catecholamine and phenethylamine families. It is an amine synthesized ...

serotonin Serotonin (), also known as 5-hydroxytryptamine (5-HT), is a monoamine neurotransmitter with a wide range of functions in both the central nervous system (CNS) and also peripheral tissues. It is involved in mood, cognition, reward, learning, ...

, and

adrenergic receptor The adrenergic receptors or adrenoceptors are a class of G protein-coupled receptors that are targets of many catecholamines like norepinephrine (noradrenaline) and epinephrine (adrenaline) produced by the body, but also many medications like b ...

s. 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 Prolactin (PRL), also known as lactotropin and mammotropin, is a protein best known for its role in enabling mammals to produce milk. It is influential in over 300 separate processes in various vertebrates, including humans. Prolactin is secr ...

levels, while interactions with serotonin receptors are thought to be principally involved in its effectiveness for

. It is very similar in

chemical structure A chemical structure of a molecule is a spatial arrangement of its atoms and their chemical bonds. Its determination includes a chemist's specifying the molecular geometry and, when feasible and necessary, the electronic structure of the target m ...

lysergic acid diethylamide Lysergic acid diethylamide, commonly known as LSD (from German ; often referred to as acid or lucy), is a Semisynthesis, semisynthetic, Hallucinogen, hallucinogenic compound derived from ergot, known for its powerful psychological effects and ...

(LSD).

Medical uses

Lisuride is used to lower

and, in low doses, to prevent

attacks. The use of lisuride as initial antiparkinsonian medication for

has been advocated, delaying the need for

levodopa Levodopa, also known as L-DOPA and sold under many brand names, is a dopaminergic medication which is used in the treatment of Parkinson's disease (PD) and certain other conditions like dopamine-responsive dystonia and restless legs syndrome. ...

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 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 malig ...

Side effects

s of lisuride include

and lowered blood pressure, among others.

Pharmacology

Pharmacodynamics

Lisuride is a

ligand In coordination chemistry, a ligand is an ion or molecule with a functional group that binds to a central metal atom to form a coordination complex. The bonding with the metal generally involves formal donation of one or more of the ligand's el ...

dopamine Dopamine (DA, a contraction of 3,4-dihydroxyphenethylamine) is a neuromodulatory molecule that plays several important roles in cells. It is an organic chemical of the catecholamine and phenethylamine families. It is an amine synthesized ...

, and

s as well as the histamine H₁ receptor. It has sub-

nanomolar Molar concentration (also called molarity, amount concentration or substance concentration) is the number of moles of solute per liter of solution. Specifically, It is a measure of the concentration of a chemical species, in particular, of a so ...

affinity Affinity may refer to: Commerce, finance and law * Affinity (law), kinship by marriage * Affinity analysis, a market research and business management technique * Affinity Credit Union, a Saskatchewan-based credit union * Affinity Equity Pa ...

for the dopamine D₂, and D₃ receptors, serotonin 5-HT_1A and 5-HT_1D receptors, and α_2A-, α_2B-, and α_2C-adrenergic receptors, and low-nanomolar affinity for the dopamine D₁, D₄, and D₅ receptors, serotonin 5-HT_2A, 5-HT_2B, and 5-HT_2C receptors, α_1A-, α_1B-, and α_1D-adrenergic receptors, and histamine H₁ receptor. Lisuride is a

partial agonist In pharmacology, partial agonists are drugs that bind to and activate a given Receptor (biochemistry), receptor, but have only partial Intrinsic activity, efficacy at the receptor relative to a full agonist. They may also be considered Ligand (bio ...

of the D₂, D₃, D₄, 5-HT_2A, 5-HT_2C, 5-HT_5A, and H₁ receptors, a full or near-full agonist of the 5-HT_1A, 5-HT_1B, and 5-HT_1D receptors, and a

silent antagonist A receptor antagonist is a type of receptor ligand or drug that blocks or dampens a biological response by binding to and blocking a receptor rather than activating it like an agonist. Antagonist drugs interfere in the natural operation of recep ...

of the 5-HT_2B receptor and α_1A-, α_2A-, α_2B-, and α_2C-adrenergic receptors. 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

(LSD; ''N'',''N''-diethyllysergamide) and acts as a partial agonist of the serotonin 5-HT_2A receptor likewise, it lacks the psychedelic effects of LSD and hence is non-

hallucinogen Hallucinogens, also known as psychedelics, entheogens, or historically as psychotomimetics, are a large and diverse class of psychoactive drugs that can produce altered states of consciousness characterized by major alterations in thought, mo ...

ic. Research suggests that the lack of psychedelic effects with lisuride may arise from biased agonism of the 5-HT_2A receptor. Stimulation of the 5-HT_2A protomer within the 5-HT_2A– mGlu2 receptor complex evokes psychedelic effects, while these effects do not occur during sole stimulation of

monomer A monomer ( ; ''mono-'', "one" + '' -mer'', "part") is a molecule that can react together with other monomer molecules to form a larger polymer chain or two- or three-dimensional network in a process called polymerization. Classification Chemis ...

ic 5-HT_2A receptors. Accordingly, different

G protein G proteins, also known as guanine nucleotide-binding proteins, are a Protein family, family of proteins that act as molecular switches inside cells, and are involved in transmitting signals from a variety of stimuli outside a cell (biology), ...

s are involved. Lisuride behaves as an agonist at the 5-HT_2A receptor monomer. Since it competitively antagonizes the effects of LSD, it may be regarded as a protomer antagonist of the 5-HT_2A–mGluR

heteromer A heteromer is something that consists of different parts; the antonym of homomeric. Examples are: Biology * Spinal neurons that pass over to the opposite side of the spinal cord. * A protein complex that contains two or more different polypeptide ...

GPCR oligomer A GPCR oligomer is a protein complex that consists of a small number ( ''oligoi'' "a few", ''méros'' "part, piece, component") of G protein-coupled receptors (GPCRs). It is held together by covalent bonds or by intermolecular forces. The subun ...

s 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-HT_2A–mGlu₂ dimers may not be essential for psychedelic effects. Lisuride shows weak or no G_q pathway recruitment and this may be responsible for its non-hallucinogenic nature. Alternatively, lisuride is an extremely potent serotonin 5-HT_1A receptor agonist, and this might inhibit serotonin 5-HT_2A receptor-mediated hallucinogenic effects. Although lisuride has widely been said to be non-hallucinogenic, this may not actually be true. Lisuride has been associated with incidence of

visual The visual system is the physiological basis of visual perception (the ability to detect and process light). The system detects, transduces and interprets information concerning light within the visible range to construct an image and buil ...

and

auditory hallucination An auditory hallucination, or paracusia, is a form of hallucination that involves perceiving sounds without auditory stimulus. While experiencing an auditory hallucination, the affected person hears a sound or sounds that did not come from the ...

s, sensory disturbances,

delusion A delusion is a fixed belief that is not amenable to change in light of conflicting evidence. As a pathology, it is distinct from a belief based on false or incomplete information, confabulation, dogma, illusion, hallucination, or some other m ...

s, and other

ic effects at high doses. It may simply be that typical therapeutic doses of lisuride are too low to adequately engage the serotonin 5-HT_2A receptor and produce hallucinogenic effects but that hallucinogenic effects can be produced at higher doses. Both serotonin 5-HT_2A receptor agonism and dopamine D₂ receptor agonism might contribute to the hallucinogenic effects of lisuride. Lisuride's potent activities at other receptors besides the serotonin 5-HT_2A receptor and its associated prominent side effects at higher doses, like

blurred vision Blurred vision is an ocular symptom where vision becomes less precise and there is added difficulty to resolve fine details. Temporary blurred vision may involve dry eyes, eye infections, alcohol poisoning, hypoglycemia, or low blood pressur ...

, and

anxiety Anxiety is an emotion characterised by an unpleasant state of inner wikt:turmoil, turmoil and includes feelings of dread over Anticipation, anticipated events. Anxiety is different from fear in that fear is defined as the emotional response ...

, may limit its potential for being dosed high enough to produce hallucinogenic effects. In animals, lisuride partially to fully substitutes for LSD and other psychedelics in drug discrimination tests in rodents and monkeys, but does not produce the

head-twitch response 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 in association with serotonin 5-HT2A receptor activation. Serotonergic psychedelics like lys ...

in rodents. However, lisuride does produce the head-twitch response in the least shrew, a non-rodent species that is said to be highly sensitive to serotonin 5-HT_2A receptor agonists. When a modified drug discrimination paradigm is employed in which animals are trained to discriminate two training drugs (lisuride and LSD) and vehicle however, lisuride no longer substitutes for LSD. Lisuride dose-dependently suppresses

levels due to its dopaminergic activity. As an antagonist of the serotonin 5-HT_2B receptor, lisuride has no risk of cardiac valvulopathy, in contrast to related ergolines like

pergolide 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 do ...

and

cabergoline 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. Cabergoline is an ...

. Minute amounts of lisuride suppress the firing of dorsal raphe serotonergic neurons, presumably due to agonist activity at 5-HT_1A receptors. 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.

Pharmacokinetics

Absorption Absorption may refer to: Chemistry and biology *Absorption (biology), digestion **Absorption (small intestine) *Absorption (chemistry), diffusion of particles of gas or liquid into liquid or solid materials *Absorption (skin), a route by which su ...

of lisuride from the

gastrointestinal tract The gastrointestinal tract (GI tract, digestive tract, alimentary canal) is the tract or passageway of the Digestion, digestive system that leads from the mouth to the anus. The tract is the largest of the body's systems, after the cardiovascula ...

with

oral administration Oral administration is a route of administration whereby a substance is taken through the Human mouth, mouth, swallowed, and then processed via the digestive system. This is a common route of administration for many medications. Oral administ ...

is complete. The

absolute bioavailability In pharmacology, bioavailability is a subcategory of absorption and is the fraction (%) of an administered drug that reaches the systemic circulation. By definition, when a medication is administered intravenously, its bioavailability is 100%. H ...

of lisuride is 10 to 20% due to high

first-pass metabolism The first pass effect (also known as first-pass metabolism or presystemic metabolism) is a phenomenon of drug metabolism at a specific location in the body which leads to a reduction in the concentration of the active drug before it reaches the ...

. The

plasma protein binding Plasma protein binding refers to the degree to which medications attach to blood proteins within the blood plasma. A drug's efficacy may be affected by the degree to which it binds. The less bound a drug is, the more efficiently it can traverse o ...

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 Biological half-life (elimination half-life, pharmacological half-life) is the time taken for concentration of a biological substance (such as a medication) to decrease from its maximum concentration ( Cmax) to half of Cmax in the blood plasma. ...

of lisuride is approximately 2 hours. This is shorter than most other

dopamine agonist 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 ...

s. Lisuride has more than 15 known

metabolite In biochemistry, a metabolite is an intermediate or end product of metabolism. The term is usually used for small molecules. Metabolites have various functions, including fuel, structure, signaling, stimulatory and inhibitory effects on enzymes, c ...

Chemistry

Lisuride, also known as 1,1-diethyl-3-(6-methyl-9,10-didehydroergolin-8α-yl)urea, is an

derivative In mathematics, the derivative is a fundamental tool that quantifies the sensitivity to change of a function's output with respect to its input. The derivative of a function of a single variable at a chosen input value, when it exists, is t ...

. It is almost identical in

(LSD), except that LSD's 8-position carboxamide

group A group is a number of persons or things that are located, gathered, or classed together. Groups of people * Cultural group, a group whose members share the same cultural identity * Ethnic group, a group whose members share the same ethnic iden ...

has been replaced with a

urea Urea, also called carbamide (because it is a diamide of carbonic acid), is an organic compound with chemical formula . This amide has two Amine, amino groups (–) joined by a carbonyl functional group (–C(=O)–). It is thus the simplest am ...

group and the 8-position

stereochemistry Stereochemistry, a subdiscipline of chemistry, studies the spatial arrangement of atoms that form the structure of molecules and their manipulation. The study of stereochemistry focuses on the relationships between stereoisomers, which are defined ...

is inverted. Lisuride is described as the

free base In chemistry, a free base (freebase, free-base) is a term for the neutral form of an amine or other Lewis base. The term is used in the pharmaceutical industry in contrast to salt-based formulations like hydrochlorides. The amine is often an ...

and as the hydrogen

maleate Maleic acid or ''cis''-butenedioic acid is an organic compound that is a dicarboxylic acid, a molecule with two carboxyl groups. Its chemical formula is HO2CCH=CHCO2H. Maleic acid is the ''cis'' isomer of butenedioic acid, whereas fumaric acid ...

salt In common usage, salt is a mineral composed primarily of sodium chloride (NaCl). When used in food, especially in granulated form, it is more formally called table salt. In the form of a natural crystalline mineral, salt is also known as r ...

Analogues

Bromination In chemistry, halogenation is a chemical reaction which introduces one or more halogens into a chemical compound. Halide-containing compounds are pervasive, making this type of transformation important, e.g. in the production of polymers, drugs ...

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

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. It was marketed by the early 1970s.

Society and culture

Generic names

''Lisuride'' is the and ''lysuride'' is the .

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 Egypt ( , ), officially the Arab Republic of Egypt, is a country spanning the Northeast Africa, northeast corner of Africa and Western Asia, southwest corner of Asia via the Sinai Peninsula. It is bordered by the Mediterranean Sea to northe ...

France France, officially the French Republic, is a country located primarily in Western Europe. Overseas France, Its overseas regions and territories include French Guiana in South America, Saint Pierre and Miquelon in the Atlantic Ocean#North Atlan ...

Italy Italy, officially the Italian Republic, is a country in Southern Europe, Southern and Western Europe, Western Europe. It consists of Italian Peninsula, a peninsula that extends into the Mediterranean Sea, with the Alps on its northern land b ...

Kuwait Kuwait, officially the State of Kuwait, is a country in West Asia and the geopolitical region known as the Middle East. It is situated in the northern edge of the Arabian Peninsula at the head of the Persian Gulf, bordering Iraq to Iraq–Kuwait ...

Lebanon Lebanon, officially the Republic of Lebanon, is a country in the Levant region of West Asia. Situated at the crossroads of the Mediterranean Basin and the Arabian Peninsula, it is bordered by Syria to the north and east, Israel to the south ...

Mexico Mexico, officially the United Mexican States, is a country in North America. It is the northernmost country in Latin America, and borders the United States to the north, and Guatemala and Belize to the southeast; while having maritime boundar ...

New Zealand New Zealand () is an island country in the southwestern Pacific Ocean. It consists of two main landmasses—the North Island () and the South Island ()—and List of islands of New Zealand, over 600 smaller islands. It is the List of isla ...

, and

Pakistan Pakistan, officially the Islamic Republic of Pakistan, is a country in South Asia. It is the List of countries and dependencies by population, fifth-most populous country, with a population of over 241.5 million, having the Islam by country# ...

. Lisuride is not currently available in the

United States The United States of America (USA), also known as the United States (U.S.) or America, is a country primarily located in North America. It is a federal republic of 50 U.S. state, states and a federal capital district, Washington, D.C. The 48 ...

, 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

. 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 A transdermal patch is a medicated adhesive patch that is placed on the skin to deliver a specific Dose (biochemistry), dose of medication through the skin and into the bloodstream. An advantage of a transdermal drug delivery route over ot ...

and

subcutaneous implant In medicine, a subcutaneous implant is an implant (medicine), implant that is delivered under the skin into the subcutaneous tissue, subcutaneous tissue (biology), tissue by surgery or injection (medicine), injection and is used to deliver a drug ...

for the treatment of Parkinson's disease,

restless legs syndrome Restless legs syndrome (RLS), also known as Willis–Ekbom disease (WED), is a neurological disorder, usually chronic, that causes an overwhelming urge to move one's legs. There is often an unpleasant feeling in the legs that improves temporaril ...

, and

dyskinesia Dyskinesia refers to a category of movement disorders that are characterized by involuntary muscle movements, including movements similar to tics or chorea and diminished voluntary movements. Dyskinesia can be anything from a slight tremor of t ...

s in the 2000s and 2010s, but development was discontinued.

References

{{Ergolines 5-HT1A agonists 5-HT1B agonists 5-HT1D agonists 5-HT2B antagonists 5-HT2C agonists Adrenergic receptor modulators Alpha-1 blockers Alpha-2 blockers Antimigraine drugs D1 receptor agonists D2 receptor agonists D3 receptor agonists D4 receptor agonists Dopamine receptor modulators Ergolines Hallucinogen antidotes Histamine agonists Non-hallucinogenic 5-HT2A receptor agonists Prolactin inhibitors Psychedelic drugs Serotonin receptor modulators Ureas