Delving into the Latest Updates on Lisuride Maleate with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

Lisuride, Lisuride TDS, Lisuride maleate (JAN)

+ [5]

Target

5-HT1A receptor x 5-HT2A receptor x 5-HT2B receptor x 5-HT2C receptor x D2 receptor

Mechanism

5-HT1A receptor agonists(Serotonin 1a (5-HT1a) receptor agonists), 5-HT2A receptor agonists(Serotonin 2a (5-HT2a) receptor agonists), 5-HT2B receptor agonists(Serotonin 2b (5-HT2b) receptor agonists)

+ [2]

Therapeutic Areas

Nervous System DiseasesEndocrinology and Metabolic DiseaseCongenital Disorders+ [1]

Active Indication

Parkinson DiseaseFragile X Syndrome

Inactive Indication

Restless Legs Syndrome

Originator Organization

Bayer Schering Pharma AG

Active Organization

Neuroventi Co., Ltd.

Inactive Organization

axxonis Pharma AG

Drug Highest PhaseApproved

First Approval Date-

RegulationOrphan Drug (US)

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Structure

Molecular FormulaC20H26N4O

InChIKeyBKRGVLQUQGGVSM-KBXCAEBGSA-N

CAS Registry18016-80-3

View All Structures (2)

AbstractDravet syndrome is a severe genetic epilepsy primarily caused by de novo mutations in a voltage-activated sodium channel gene (SCN1A). Patients face life-threatening seizures that are largely resistant to available anti-seizure medications. Preclinical Dravet syndrome animal models are a valuable tool to identify candidate anti-seizure medications for these patients. Among these, scn1lab mutant zebrafish, exhibiting spontaneous seizure-like activity, are particularly amenable to large-scale drug screening. Thus far, we have screened more than 3000 drug candidates in scn1lab zebrafish mutants, identifying valproate, stiripentol, and fenfluramine e.g. Food and Drug Administration-approved drugs, with clinical application in the Dravet syndrome population. Successful phenotypic screening in scn1lab mutant zebrafish is rigorous and consists of two stages: (i) a locomotion-based assay measuring high-velocity convulsive swim behaviour and (ii) an electrophysiology-based assay, using in vivo local field potential recordings, to quantify electrographic seizure-like events. Historically, nearly 90% of drug candidates fail during translation from preclinical models to the clinic. With such a high failure rate, it becomes necessary to address issues of replication and false positive identification. Leveraging our scn1lab zebrafish assays is one approach to address these problems. Here, we curated a list of nine anti-seizure drug candidates recently identified by other groups using preclinical Dravet syndrome models: 1-Ethyl-2-benzimidazolinone, AA43279, chlorzoxazone, donepezil, lisuride, mifepristone, pargyline, soticlestat and vorinostat. First-stage locomotion-based assays in scn1lab mutant zebrafish identified only 1-Ethyl-2-benzimidazolinone, chlorzoxazone and lisuride. However, second-stage local field potential recording assays did not show significant suppression of spontaneous electrographic seizure activity for any of the nine anti-seizure drug candidates. Surprisingly, soticlestat induced frank electrographic seizure-like discharges in wild-type control zebrafish. Taken together, our results failed to replicate clear anti-seizure efficacy for these drug candidates highlighting a necessity for strict scientific standards in preclinical identification of anti-seizure medications.

08 Mar 2024·ACS Pharmacology & Translational Science

Comparative Pharmacological Effects of Lisuride and Lysergic Acid Diethylamide Revisited

Article

Author: Partilla, John S. ; Stove, Christophe P. ; Baumann, Michael H. ; Pottie, Eline ; Glatfelter, Grant C.

Lisuride is a non-psychedelic serotonin (5-HT) 2A receptor (5-HT_2A) agonist and analogue of the psychedelic lysergic acid diethylamide (LSD). Lisuride also acts as an agonist at the serotonin 1A receptor (5-HT_1A), a property known to counter psychedelic effects. Here, we tested whether lisuride lacks psychedelic activity due to a dual mechanism: (1) partial agonism at 5-HT_2A and (2) potent agonism at 5-HT_1A. The in vitro effects of lisuride, LSD, and related analogues on 5-HT_2A signaling were characterized by using miniGα_q and β-arrestin 2 recruitment assays. The 5-HT_1A- and 5-HT_2A-mediated effects of lisuride and LSD were also compared in male C57BL/6J mice. The in vitro results confirmed that LSD is an agonist at 5-HT_2A, with high efficacy and potency for recruiting miniGα_q and β-arrestin 2. By contrast, lisuride displayed partial efficacy for both functional end points (6-52% of 5-HT or LSD E_max) and antagonized the effects of LSD. The mouse experiments demonstrated that LSD induces head twitch responses (HTRs)(ED₅₀ = 0.039 mg/kg), while lisuride suppresses HTRs (ED₅₀ = 0.006 mg/kg). Lisuride also produced potent hypothermia and hypolocomotion (ED₅₀ = 0.008-0.023 mg/kg) that was blocked by the 5-HT_1A antagonist WAY100635 (3 mg/kg). Blockade of 5-HT_1A prior to lisuride restored basal HTRs, but it failed to increase HTRs above baseline levels. HTRs induced by LSD were blocked by lisuride (0.03 mg/kg) or the 5-HT_1A agonist 8-OH-DPAT (1 mg/kg). Overall, our findings show that lisuride is an ultrapotent 5-HT_1A agonist in C57BL/6J mice, limiting its use as a 5-HT_2A ligand in mouse studies examining acute drug effects. Results also indicate that the 5-HT_2A partial agonist-antagonist activity of lisuride explains its lack of psychedelic effects.

01 Mar 2024·Neuropsychopharmacology

Antidepressant-like effects of psychedelics in a chronic despair mouse model: is the 5-HT2A receptor the unique player?

Article

Author: Marin, Philippe ; Bécamel, Carine ; Bockaert, Joël ; Sekssaoui, Mehdi

AbstractMajor depressive disorder (MDD) is one of the most disabling psychiatric disorders in the world. First-line treatments such as selective serotonin reuptake inhibitors (SSRIs) still have many limitations, including a resistance to treatment in 30% of patients and a delayed clinical benefit that is observed only after several weeks of treatment. Increasing clinical evidence indicates that the acute administration of psychedelic agonists of the serotonin 5-HT2A receptor (5-HT2AR), such as psilocybin, to patients with MDD induce fast antidepressant effects, which persist up to five weeks after the treatment. However, the involvement of the 5-HT2AR in these antidepressant effects remains controversial. Furthermore, whether the hallucinogenic properties of 5-HT2AR agonists are mandatory to their antidepressant activity is still an open question. Here, we addressed these issues by investigating the effect of two psychedelics of different chemical families, DOI and psilocybin, and a non-hallucinogenic 5-HT2AR agonist, lisuride, in a chronic despair mouse model exhibiting a robust depressive-like phenotype. We show that a single injection of each drug to wild type mice induces anxiolytic- and antidepressant-like effects in the novelty-suppressed feeding, sucrose preference and forced swim tests, which last up to 15 days. DOI and lisuride administration did not produce antidepressant-like effects in 5-HT2A−/− mice, whereas psilocybin was still effective. Moreover, neither 5-HT1AR blockade nor dopamine D1 or D2 receptor blockade affected the antidepressant-like effects of psilocybin in 5-HT2A−/− mice. Collectively, these findings indicate that 5-HT2AR agonists can produce antidepressant-like effects independently of hallucinogenic properties through mechanisms involving or not involving the receptor.

100 Deals associated with Lisuride Maleate

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External Link

KEGG	Wiki	ATC	Drug Bank
D01462	Lisuride Maleate	G02CB02 N02CA07	DB00589

R&D Status

Approved

10 top approved records.

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Indication	Country/Location	Organization	Date
Parkinson Disease	-	-	-

Developing

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Restless Legs Syndrome	Phase 1	DE	axxonis Pharma AG	23 Aug 2006
Parkinson Disease	Phase 1	DE	axxonis Pharma AG	01 Jul 2006
Fragile X Syndrome	Preclinical	KR	Neuroventi Co., Ltd.	27 Oct 2022