Discovery of Trace Amine-Associated Receptor 1 (TAAR1) Agonist 2-(5-(4′-Chloro-[1,1′-biphenyl]-4-yl)-4H-1,2,4-triazol-3-yl)ethan-1-amine (LK00764) for the Treatment of Psychotic Disorders

Standard

Discovery of Trace Amine-Associated Receptor 1 (TAAR1) Agonist 2-(5-(4′-Chloro-[1,1′-biphenyl]-4-yl)-4H-1,2,4-triazol-3-yl)ethan-1-amine (LK00764) for the Treatment of Psychotic Disorders. / Krasavin, Mikhail ; Lukin, Alexey ; Sukhanov, Ilya ; Gerasimov, Andrey S. ; Kuvarzin, Savelii ; Efimova, Evgeniya V. ; Dorofeikova , Mariia ; Nichugovskaya, Anna ; Matveev, Andrey ; Onokhin, Kirill ; Zakharov, Konstantin ; Gureev, Maxim ; Gainetdinov , Raul R. .

в: Biomolecules, Том 12, № 11, 1650, 11.2022.

Результаты исследований: Научные публикации в периодических изданиях › статья › Рецензирование

BibTeX

@article{1b6fd42a50ae4495a93d717775ef556e,

title = "Discovery of Trace Amine-Associated Receptor 1 (TAAR1) Agonist 2-(5-(4′-Chloro-[1,1′-biphenyl]-4-yl)-4H-1,2,4-triazol-3-yl)ethan-1-amine (LK00764) for the Treatment of Psychotic Disorders",

abstract = "A focused in-house library of about 1000 compounds comprising various heterocyclic motifs in combination with structural fragments similar to β-phenylethylamine or tyramine was screened for the agonistic activity towards trace amine-associated receptor 1 (TAAR1). The screening yielded two closely related hits displaying EC50 values in the upper submicromolar range. Extensive analog synthesis and testing for TAAR1 agonism in a BRET-based cellular assay identified compound 62 (LK00764) with EC50 = 4.0 nM. The compound demonstrated notable efficacy in such schizophrenia-related in vivo tests as MK-801-induced hyperactivity and spontaneous activity in rats, locomotor hyperactivity of dopamine transporter knockout (DAT-KO) rats, and stress-induced hyperthermia (i.p. administration). Further preclinical studies are necessary to evaluate efficacy, safety and tolerability of this potent TAAR1 agonist for the potential development of this compound as a new pharmacotherapy option for schizophrenia and other psychiatric disorders.",

keywords = "schizophrenia, trace amine-associated receptor 1, agonism, 1,2,4-triazoles, dopamine transporter knockout rats, dopamine, MK-801-induced hyperactivity, spontaneous activity, locomotor hyperactivity, stress-induced hyperthermia",

author = "Mikhail Krasavin and Alexey Lukin and Ilya Sukhanov and Gerasimov, {Andrey S.} and Savelii Kuvarzin and Efimova, {Evgeniya V.} and Mariia Dorofeikova and Anna Nichugovskaya and Andrey Matveev and Kirill Onokhin and Konstantin Zakharov and Maxim Gureev and Gainetdinov, {Raul R.}",

year = "2022",

month = nov,

doi = "https://doi.org/10.3390/biom12111650",

language = "English",

volume = "12",

journal = "Biomolecules",

issn = "2218-273X",

publisher = "MDPI AG",

number = "11",

}

RIS

TY - JOUR

T1 - Discovery of Trace Amine-Associated Receptor 1 (TAAR1) Agonist 2-(5-(4′-Chloro-[1,1′-biphenyl]-4-yl)-4H-1,2,4-triazol-3-yl)ethan-1-amine (LK00764) for the Treatment of Psychotic Disorders

AU - Krasavin, Mikhail

AU - Lukin, Alexey

AU - Sukhanov, Ilya

AU - Gerasimov, Andrey S.

AU - Kuvarzin, Savelii

AU - Efimova, Evgeniya V.

AU - Dorofeikova , Mariia

AU - Nichugovskaya, Anna

AU - Matveev, Andrey

AU - Onokhin, Kirill

AU - Zakharov, Konstantin

AU - Gureev, Maxim

AU - Gainetdinov , Raul R.

PY - 2022/11

Y1 - 2022/11

N2 - A focused in-house library of about 1000 compounds comprising various heterocyclic motifs in combination with structural fragments similar to β-phenylethylamine or tyramine was screened for the agonistic activity towards trace amine-associated receptor 1 (TAAR1). The screening yielded two closely related hits displaying EC50 values in the upper submicromolar range. Extensive analog synthesis and testing for TAAR1 agonism in a BRET-based cellular assay identified compound 62 (LK00764) with EC50 = 4.0 nM. The compound demonstrated notable efficacy in such schizophrenia-related in vivo tests as MK-801-induced hyperactivity and spontaneous activity in rats, locomotor hyperactivity of dopamine transporter knockout (DAT-KO) rats, and stress-induced hyperthermia (i.p. administration). Further preclinical studies are necessary to evaluate efficacy, safety and tolerability of this potent TAAR1 agonist for the potential development of this compound as a new pharmacotherapy option for schizophrenia and other psychiatric disorders.

AB - A focused in-house library of about 1000 compounds comprising various heterocyclic motifs in combination with structural fragments similar to β-phenylethylamine or tyramine was screened for the agonistic activity towards trace amine-associated receptor 1 (TAAR1). The screening yielded two closely related hits displaying EC50 values in the upper submicromolar range. Extensive analog synthesis and testing for TAAR1 agonism in a BRET-based cellular assay identified compound 62 (LK00764) with EC50 = 4.0 nM. The compound demonstrated notable efficacy in such schizophrenia-related in vivo tests as MK-801-induced hyperactivity and spontaneous activity in rats, locomotor hyperactivity of dopamine transporter knockout (DAT-KO) rats, and stress-induced hyperthermia (i.p. administration). Further preclinical studies are necessary to evaluate efficacy, safety and tolerability of this potent TAAR1 agonist for the potential development of this compound as a new pharmacotherapy option for schizophrenia and other psychiatric disorders.

KW - schizophrenia

KW - trace amine-associated receptor 1

KW - agonism

KW - 1,2,4-triazoles

KW - dopamine transporter knockout rats

KW - dopamine

KW - MK-801-induced hyperactivity

KW - spontaneous activity

KW - locomotor hyperactivity

KW - stress-induced hyperthermia

U2 - https://doi.org/10.3390/biom12111650

DO - https://doi.org/10.3390/biom12111650

M3 - Article

VL - 12

JO - Biomolecules

JF - Biomolecules

SN - 2218-273X

IS - 11

M1 - 1650

ER -

ID: 101521814