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Hit-to-Lead Optimization of Mouse Trace Amine Associated Receptor 1 (mTAAR1) Agonists with a Diphenylmethane-Scaffold: Design, Synthesis, and Biological Study

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Department of Pathology, University of Pisa, 56126 Pisa, Italy
Department of Pharmacy, University of Pisa, 56126, Pisa, Italy
§ Department of Neuroscience and Brain Technologies, Istituto Italiano di Tecnologia, 16163 Genova, Italy
Department of NEUROFARBA, Section of Pharmacology, University of Florence, 50139 Florence, Italy
Department of Pharmacy, University of Genoa, 16126, Genoa, Italy
# Institute of Translational Biomedicine, St. Petersburg State University, St. Petersburg, 199034, Russia
Skolkovo Institute of Science and Technology (Skoltech), Skolkovo, Moscow Region, 143025, Russia
*For S.R.: phone, +39 050 2219582; fax, +39 050 2219577; E-mail, [email protected]
*For G.C.: phone, +39 050 2218677; E-mail, [email protected]
Cite this: J. Med. Chem. 2016, 59, 21, 9825–9836
Publication Date (Web):October 12, 2016
Copyright © 2016 American Chemical Society

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    Abstract Image

    The trace amine-associated receptor 1 (TAAR1) is a G-protein-coupled receptors (GPCR) potently activated by a variety of molecules besides trace amines (TAs), including thyroid hormone-derivatives like 3-iodothyronamine (T1AM), catechol-O-methyltransferase products like 3-methoxytyramine, and amphetamine-related compounds. Accordingly, TAAR1 is considered a promising target for medicinal development. To gain more insights into TAAR1 physiological functions and validation of its therapeutic potential, we recently developed a new class of thyronamine-like derivatives. Among them compound SG2 showed high affinity and potent agonist activity at mouse TAAR1. In the present work, we describe design, synthesis, and SAR study of a new series of compounds (116) obtained by introducing specific structural changes at key points of our lead compound SG2 skeleton. Five of the newly synthesized compounds displayed mTAAR1 agonist activity higher than both SG2 and T1AM. Selected diphenylmethane analogues, namely 1 and 2, showed potent functional activity in in vitro and in vivo models.

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    The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.jmedchem.6b01092.

    • Synthetic pathways and procedures for the preparation of compound 34 and derivatives 1116, 1H NMR and 13C NMR spectra of final compounds (PDF)

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    7. Josef Köhrle, Heike Biebermann. 3-Iodothyronamine—A Thyroid Hormone Metabolite With Distinct Target Profiles and Mode of Action. Endocrine Reviews 2019, 40 (2) , 602-630.
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    15. Mark D. Berry, Raul R. Gainetdinov, Marius C. Hoener, Mohammed Shahid. Pharmacology of human trace amine-associated receptors: Therapeutic opportunities and challenges. Pharmacology & Therapeutics 2017, 180 , 161-180.
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