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
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 re...
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MDPI AG
2022-11-01
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| author | 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 |
| author_facet | 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 |
| author_sort | Mikhail Krasavin |
| collection | DOAJ |
| description | 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 <b>62</b> (LK00764) with EC<sub>50</sub> = 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. |
| first_indexed | 2024-03-09T19:13:51Z |
| format | Article |
| id | doaj.art-08fe6a56360a4de292d962edb7537ab5 |
| institution | Directory Open Access Journal |
| issn | 2218-273X |
| language | English |
| last_indexed | 2024-03-09T19:13:51Z |
| publishDate | 2022-11-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Biomolecules |
| spelling | doaj.art-08fe6a56360a4de292d962edb7537ab52023-11-24T03:54:03ZengMDPI AGBiomolecules2218-273X2022-11-011211165010.3390/biom12111650Discovery 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 DisordersMikhail Krasavin0Alexey Lukin1Ilya Sukhanov2Andrey S. Gerasimov3Savelii Kuvarzin4Evgeniya V. Efimova5Mariia Dorofeikova6Anna Nichugovskaya7Andrey Matveev8Kirill Onokhin9Konstantin Zakharov10Maxim Gureev11Raul R. Gainetdinov12Department of Medicinal Chemistry, Institute of Chemistry, Saint Petersburg State University, 199034 Saint Petersburg, RussiaLomonosov Institute of Fine Chemical Technologies, MIREA—Russian Technological University, 119454 Moscow, RussiaValdman Institute of Pharmacology, Pavlov First Saint Peterburg State Medical University, 197022 Saint Petersburg, RussiaInstitute of Translational Biomedicine, Saint Petersburg State University, 199034 Saint Petersburg, RussiaInstitute of Translational Biomedicine, Saint Petersburg State University, 199034 Saint Petersburg, RussiaInstitute of Translational Biomedicine, Saint Petersburg State University, 199034 Saint Petersburg, RussiaAccellena Research and Development Inc., 88A Sredniy pr. V.O., 199106 Saint Petersburg, RussiaLomonosov Institute of Fine Chemical Technologies, MIREA—Russian Technological University, 119454 Moscow, RussiaLomonosov Institute of Fine Chemical Technologies, MIREA—Russian Technological University, 119454 Moscow, RussiaInstitute of Translational Biomedicine, Saint Petersburg State University, 199034 Saint Petersburg, RussiaAccellena Research and Development Inc., 88A Sredniy pr. V.O., 199106 Saint Petersburg, RussiaCenter of Bio- and Chemoinformatics, I.M. Sechenov First Moscow State Medical University, 119991 Moscow, RussiaInstitute of Translational Biomedicine, Saint Petersburg State University, 199034 Saint Petersburg, RussiaA 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 <b>62</b> (LK00764) with EC<sub>50</sub> = 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.https://www.mdpi.com/2218-273X/12/11/1650schizophreniatrace amine-associated receptor 1agonism1,2,4-triazolesdopamine transporter knockout ratsdopamine |
| spellingShingle | 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 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 Biomolecules schizophrenia trace amine-associated receptor 1 agonism 1,2,4-triazoles dopamine transporter knockout rats dopamine |
| title | 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 |
| title_full | 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 |
| title_fullStr | 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 |
| title_full_unstemmed | 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 |
| title_short | 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 |
| title_sort | 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 |
| topic | schizophrenia trace amine-associated receptor 1 agonism 1,2,4-triazoles dopamine transporter knockout rats dopamine |
| url | https://www.mdpi.com/2218-273X/12/11/1650 |
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