GABAA receptor agonists(Gamma-aminobutyric acid A receptor agonists), GABRA2 agonists(Gamma-aminobutyric acid A receptor alpha-2 agonists), GABRA3 agonists(Gamma-aminobutyric acid A receptor alpha-3 agonists)

Therapeutic Areas

Other Diseases

Active Indication-

Inactive Indication

Anxiety Disorders

Originator Organization

Sanofi

Active Organization-

Inactive Organization

Hoechst Pakistan Ltd.

Sanofi

Drug Highest PhaseDiscontinuedPhase 2

First Approval Date-

Regulation-

Structure

Molecular FormulaC23H20FN3O2

InChIKeyQQWHWWDIFGNCLV-UHFFFAOYSA-N

CAS Registry205881-86-3

100 Clinical Results associated with SL-651498

100 Translational Medicine associated with SL-651498

100 Patents (Medical) associated with SL-651498

Literatures (Medical) associated with SL-651498

01 Sep 2021·Toxicology and Applied PharmacologyQ3 · MEDICINE

The efficacy of γ-aminobutyric acid type A receptor (GABA AR) subtype-selective positive allosteric modulators in blocking tetramethylenedisulfotetramine (TETS)-induced seizure-like behavior in larval zebrafish with minimal sedation

Q3 · MEDICINE

Article

Author: Lein, Pamela J ; Carty, Dennis R ; Pressly, Brandon ; Yaghoobi, Bianca ; Wulff, Heike ; Mundy, Paige C

The chemical threat agent tetramethylenedisulfotetramine (TETS) is a γ-aminobutyric acid type A receptor (GABA _AR) antagonist that causes life threatening seizures. Currently, there is no specific antidote for TETS intoxication. TETS-induced seizures are typically treated with benzodiazepines, which function as nonselective positive allosteric modulators (PAMs) of synaptic GABA_ARs. The major target of TETS was recently identified as the GABA_AR α2β3γ2 subtype in electrophysiological studies using recombinantly expressed receptor combinations. Here, we tested whether these in vitro findings translate in vivo by comparing the efficacy of GABA_AR subunit-selective PAMs in reducing TETS-induced seizure behavior in larval zebrafish. We tested PAMs targeting α1, α2, α2/3/5, α6, ß2/3, ß1/2/3, and δ subunits and compared their efficacy to the benzodiazepine midazolam (MDZ). The data demonstrate that α2- and α6-selective PAMs (SL-651,498 and SB-205384, respectively) were effective at mitigating TETS-induced seizure-like behavior. Combinations of SB-205384 and MDZ or SL-651,498 and 2-261 (ß2/3-selective) mitigated TETS-induced seizure-like behavior at concentrations that did not elicit sedating effects in a photomotor behavioral assay, whereas MDZ alone caused sedation at the concentration required to stop seizure behavior. Isobologram analyses suggested that SB-205384 and MDZ interacted in an antagonistic fashion, while the effects of SL-651,498 and 2-261 were additive. These results further elucidate the molecular mechanism by which TETS induces seizures and provide mechanistic insight regarding specific countermeasures against this chemical convulsant.

30 Jun 2020·ACS OmegaQ3 · CHEMISTRY

Synthesis of 2,3-Disubstituted 4-Ethoxycarbonyl-β-carbolin-1-ones: Application to the Synthesis of SL651498 and Its Analogue

Q3 · CHEMISTRY

ArticleOA

Author: Hachiya, Iwao ; Goto, Shinsuke ; Hashimoto, Takahide ; Miura, Ryoya

Synthesis of 2,3-disubstituted 4-ethoxycarbonyl-β-carbolin-1-ones is developed using palladium-catalyzed intramolecular amination of 3-amino-4-(2-bromophenyl)-2-pyridones prepared by the conjugate addition reaction of diethyl 2-aminomalonate to alkynyl imines. The method was applied to the total syntheses of SL651498 exhibiting anxiolytic activity and its analogue.

01 Aug 2019·Pharmacology Biochemistry and BehaviorQ4 · PSYCHOLOGY

Increased sensitivity to psychostimulants and GABAergic drugs in Lsamp-deficient mice

Q4 · PSYCHOLOGY

Article

Author: Mazitov, Timur ; Philips, Mari-Anne ; Vasar, Eero ; Bregin, Aleksandr ; Innos, Jürgen ; Aug, Ingrid

Lsamp, in combinations with other members of the IgLON family of cell adhesion molecules, promotes and inhibits neurite outgrowth and synapse formation during development. Mice lacking Lsamp gene display decreased social behaviour, hyperactivity; decreased anxiety level, alongside with altered balance in GABAA receptor α1 and α2 subunits; and decreased sensitivity to amphetamine, alongside with elevated serotonin function. In human studies, Lsamp has been associated with several psychiatric diseases, including schizophrenia, and suicide. Here, we provide a more thorough characterization of the pharmacological phenotype of Lsamp-deficient mice, including testing for sensitivity to morphine, cocaine, MK-801 and ketamine. More thorougly, sensitivity to GABA modulators (diazepam, alprazolam, ethanol, pentobarbital, TP003, and SL651498) was assessed. In brief, Lsamp-deficient mice were more sensitive to the locomotor activating effects of cocaine and morphine, and hypersensitive to the sedative and muscle relaxant effects of GABA modulators, most likely reflecting enhanced function of α1 and α5 subunits of the GABAA receptor. No gross differences in sensitivity to NMDA receptor modulators were observed. Thus, as the lack of Lsamp gene leads to widespread imbalances in major neurotransmitter systems in the brain accompanied by remarkable changes in behavioural phenotype as well, Lsamp-deficient mice are a promising model for mimicking psychiatric disorders.

100 Deals associated with SL-651498

External Link

KEGG	Wiki	ATC	Drug Bank
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R&D Status

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Indication	Highest Phase	Country/Location	Organization	Date
Anxiety Disorders	Phase 2	-	Sanofi	-
Anxiety Disorders	Phase 2	FR	Hoechst Pakistan Ltd.	-

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