Discovery of Trace Amine-Associated Receptor 1 (TAAR1) Agonist 2-(5-(4′-Chloro-[1,1′-biphenyl]-4-yl)-4<i>H</i>-1,2,4-triazol-3-yl)ethan-1-amine (LK00764) for the Treatment of Psychotic Disorders
Mikhail Krasavin,
Alexey Lukin,
Ilya Sukhanov,
Andrey S. Gerasimov,
Savelii Kuvarzin,
Evgeniya V. Efimova,
Mariia Dorofeikova,
Anna Nichugovskaya,
Andrey Matveev,
Kirill Onokhin,
Konstantin Zakharov,
Maxim Gureev,
Raul R. Gainetdinov
Affiliations
Mikhail Krasavin
Department of Medicinal Chemistry, Institute of Chemistry, Saint Petersburg State University, 199034 Saint Petersburg, Russia
Alexey Lukin
Lomonosov Institute of Fine Chemical Technologies, MIREA—Russian Technological University, 119454 Moscow, Russia
Ilya Sukhanov
Valdman Institute of Pharmacology, Pavlov First Saint Peterburg State Medical University, 197022 Saint Petersburg, Russia
Andrey S. Gerasimov
Institute of Translational Biomedicine, Saint Petersburg State University, 199034 Saint Petersburg, Russia
Savelii Kuvarzin
Institute of Translational Biomedicine, Saint Petersburg State University, 199034 Saint Petersburg, Russia
Evgeniya V. Efimova
Institute of Translational Biomedicine, Saint Petersburg State University, 199034 Saint Petersburg, Russia
Mariia Dorofeikova
Accellena Research and Development Inc., 88A Sredniy pr. V.O., 199106 Saint Petersburg, Russia
Anna Nichugovskaya
Lomonosov Institute of Fine Chemical Technologies, MIREA—Russian Technological University, 119454 Moscow, Russia
Andrey Matveev
Lomonosov Institute of Fine Chemical Technologies, MIREA—Russian Technological University, 119454 Moscow, Russia
Kirill Onokhin
Institute of Translational Biomedicine, Saint Petersburg State University, 199034 Saint Petersburg, Russia
Konstantin Zakharov
Accellena Research and Development Inc., 88A Sredniy pr. V.O., 199106 Saint Petersburg, Russia
Maxim Gureev
Center of Bio- and Chemoinformatics, I.M. Sechenov First Moscow State Medical University, 119991 Moscow, Russia
Raul R. Gainetdinov
Institute of Translational Biomedicine, Saint Petersburg State University, 199034 Saint Petersburg, Russia
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.
