# Lisuride

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. 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.

## 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.

## Side effects

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

## Pharmacology
### Pharmacodynamics

Lisuride is a ligand of dopamine, serotonin, and adrenergic receptors as well as the histamine H$_1$ receptor. It has sub-nanomolar affinity for the dopamine D$_2$, and D$_3$ 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 D$_1$, D$_4$, and D$_5$ receptors, serotonin 5-HT$_{2A}$, 5-HT$_{2B}$, and 5-HT$_{2C}$ receptors, α$_{1A}$-, α$_{1B}$-, and α$_{1D}$-adrenergic receptors, and histamine H$_1$ receptor. Lisuride is a partial agonist of the D$_2$, D$_3$, D$_4$, 5-HT$_{2A}$, 5-HT$_{2C}$, 5-HT$_{5A}$, and H$_1$ receptors, a full or near-full agonist of the 5-HT$_{1A}$, 5-HT$_{1B}$, and 5-HT$_{1D}$ receptors, and a silent antagonist 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 D$_2$ 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-HT$_{2A}$ receptor likewise, it lacks the psychedelic effects of LSD and hence is non-hallucinogenic. Research suggests that the lack of psychedelic effects with lisuride arises 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 monomeric 5-HT$_{2A}$ receptors. Accordingly, different G proteins 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. 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-HT$_{2A}$–mGlu$_2$ 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.
Lisuride dose-dependently suppresses prolactin levels due to its dopaminergic activity. As an antagonist of the 5-HT$_{2B}$ 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-HT$_{1A}$ receptors. Noradrenergic neurons of the locus coeruleus were accelerated by the drug at somewhat higher doses, consistent with α$_1$-adrenergic receptor antagonist activity. Pars compacta dopamine neurons demonstrated a variable response.
Activities of lisuride at various sites :
| Site | Affinity (K$_i$ [nM]) | Efficacy (E$_{max}$ [%]) | Action |
| D$_1$ | 65 | ? | ? |
| D$_{2S}$ | 0.34 | 55 | Partial agonist |
| D$_{2L}$ | 0.66 | 21 | Partial agonist |
| D$_3$ | 0.28 | 49 | Partial agonist |
| D$_4$ | 4.6 | 32 | Partial agonist |
| D$_5$ | 3.5 | ? | ? |
| 5-HT$_{1A}$ | 0.15 | 98 | Full agonist |
| 5-HT$_{1B}$ | 19 | 85 | Partial agonist |
| 5-HT$_{1D}$ | 0.98 | 81 | Partial agonist |
| 5-HT$_{2A}$ | 2.8 | 52 | Partial agonist |
| 5-HT$_{2B}$ | 1.3 | 0 | Silent antagonist |
| 5-HT$_{2C}$ | 6.6 | 75 | Partial agonist |
| 5-HT$_{5A}$ | ? | 11 | Partial agonist |
| α$_{1A}$ | 5.5 | 0 | Silent antagonist |
| α$_{1B}$ | 17 | ? | ? |
| α$_{1D}$ | 3.0 | ? | ? |
| α$_{2A}$ | 0.055 | 0 | Silent antagonist |
| α$_{2B}$ | 0.13 | 0 | Silent antagonist |
| α$_{2C}$ | 0.13 | 0 | Silent antagonist |
| α$_{2D}$ | 0.79 | ? | ? |
| β$_1$ | 68 | ? | ? |
| β$_2$ | 7.9 | ? | ? |
| H$_1$ | 35 | ? | Partial agonist |
| M$_1$ | >10,000 | – | – |
| Notes: All receptors are human except α$_{2D}$-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.

## 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 INNTooltip International Nonproprietary Name and lysuride is the BANTooltip British Approved Name.

### 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.