title: Hit-to-Lead Optimization of Mouse Trace Amine Associated Receptor 1 (mTAAR1) Agonists with a Diphenylmethane-Scaffold: Design, Synthesis, and Biological Study.
abstract: 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 (1-16) 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.
authors.affiliation: Department of Pathology, University of Pisa , 56126 Pisa, Italy.
authors.forename: Grazia
authors.initials: G
authors.lastname: Chiellini
authors.affiliation: Department of Pharmacy, University of Pisa , 56126, Pisa, Italy.
authors.forename: Giulia
authors.initials: G
authors.lastname: Nesi
authors.affiliation: Department of Pharmacy, University of Pisa , 56126, Pisa, Italy.
authors.forename: Simona
authors.initials: S
authors.lastname: Sestito
authors.affiliation: Department of Pharmacy, University of Pisa , 56126, Pisa, Italy.
authors.forename: Sara
authors.initials: S
authors.lastname: Chiarugi
authors.affiliation: Department of Pharmacy, University of Pisa , 56126, Pisa, Italy.
authors.forename: Massimiliano
authors.initials: M
authors.lastname: Runfola
authors.affiliation: Department of Neuroscience and Brain Technologies, Istituto Italiano di Tecnologia , 16163 Genova, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Espinoza
authors.affiliation: Department of Pathology, University of Pisa , 56126 Pisa, Italy.
authors.forename: Martina
authors.initials: M
authors.lastname: Sabatini
authors.affiliation: Department of Pathology, University of Pisa , 56126 Pisa, Italy.
authors.forename: Lorenza
authors.initials: L
authors.lastname: Bellusci
authors.affiliation: Department of NEUROFARBA, Section of Pharmacology, University of Florence , 50139 Florence, Italy.
authors.forename: Annunziatina
authors.initials: A
authors.lastname: Laurino
authors.affiliation: Department of Pharmacy, University of Genoa , 16126, Genoa, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Cichero
authors.affiliation: Institute of Translational Biomedicine, St. Petersburg State University , St. Petersburg, 199034, Russia.|Skolkovo Institute of Science and Technology (Skoltech) , Skolkovo, Moscow Region, 143025, Russia.
authors.forename: Raul R
authors.initials: RR
authors.lastname: Gainetdinov
authors.affiliation: Department of Pharmacy, University of Genoa , 16126, Genoa, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Fossa
authors.affiliation: Department of NEUROFARBA, Section of Pharmacology, University of Florence , 50139 Florence, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Raimondi
authors.affiliation: Department of Pathology, University of Pisa , 56126 Pisa, Italy.
authors.forename: Riccardo
authors.initials: R
authors.lastname: Zucchi
authors.affiliation: Department of Pharmacy, University of Pisa , 56126, Pisa, Italy.
authors.forename: Simona
authors.initials: S
authors.lastname: Rapposelli
mesh_terms: D000818:Animals; D001559:Benzhydryl Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D057809:HEK293 Cells; D056945:Hep G2 Cells; D006801:Humans; D051379:Mice; D062105:Molecular Docking Simulation; D015394:Molecular Structure; D043562:Receptors, G-Protein-Coupled / Q000819:agonists*; D013329:Structure-Activity Relationship; D000095383:Trace Amine-Associated Receptors
chemical_list: D001559:Benzhydryl Compounds; D043562:Receptors, G-Protein-Coupled; D000095383:Trace Amine-Associated Receptors; C010129:diphenylmethane