Lisuride

Pharmacodynamics

Lisuride is a ligand of dopamine, serotonin, and adrenergic receptors as well as the histamine H₁ receptor.^[6] It has sub-nanomolar affinity 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.^[6][21][22] Lisuride is a partial agonist 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 of the 5-HT_2B receptor and α_1A-, α_2A-, α_2B-, and α_2C-adrenergic receptors.^{[8][22][23][24][25]} 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-HT_2A receptor likewise,^[8] it lacks the psychedelic effects of LSD and hence is non-hallucinogenic.^[26][1] 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 monomeric 5-HT_2A receptors. Accordingly, different G proteins are involved.^[27][28] 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.^[29] 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–mGlu₂ dimers may not be essential for psychedelic effects.^[30][31] Lisuride shows weak or no G_q pathway recruitment and this may be responsible for its non-hallucinogenic nature.^[18][32] Alternatively, lisuride is an extremely potent serotonin 5-HT_1A receptor agonist, and this might inhibit serotonin 5-HT_2A receptor-mediated hallucinogenic effects.^[33]

Although lisuride has widely been said to be non-hallucinogenic, this may not actually be true.^[5][34][35] Lisuride has been associated with incidence of visual and auditory hallucinations, sensory disturbances, delusions, and other hallucinogenic effects at high doses.^[5][34][35] 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.^[5] Both serotonin 5-HT_2A receptor agonism and dopamine D₂ receptor agonism might contribute to the hallucinogenic effects of lisuride.^[5] Lisuride's potent activities at other receptors besides the serotonin 5-HT_2A receptor and its associated prominent side effects at higher doses, like nausea, hypotension, blurred vision, and anxiety, may limit its potential for being dosed high enough to produce hallucinogenic effects.^[5] 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 in rodents.^{[36][37][38][5][34][39][40]} 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.^[41][42] 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.^[37]

Lisuride dose-dependently suppresses prolactin levels due to its dopaminergic activity.^[1][43] As an antagonist of the serotonin 5-HT_2B 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-HT_1A receptors. ^[44] 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 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]

Analogues

Bromination of lisuride gives bromerguride (2-bromolisuride), which has a "reversed pharmacodynamic profile" compared to that of lisuride.^[48]

Generic names

Lisuride is the INNTooltip International Nonproprietary Name and lysuride is the BANTooltip British Approved Name.^{[45][51][46][47]}

Brand names

Lisuride has been sold under brand names including Arolac, Cuvalit, Dopagon, Dopergin, Dopergine, Eunal, Lisenil, Lizenil, Lysenyl, Proclacam, Prolacam, and Revanil.^{[45][46][47][1]}

Availability

Lisuride was previously more widely available throughout the world,^[46][1] but as of 2020 it appears to be marketed only in Egypt, France, Italy, Kuwait, Lebanon, Mexico, New Zealand, and Pakistan.^[47] Lisuride is not currently available in the United States, as the drug was not a commercial success.