title: Design, Synthesis, and Evaluation of Thyronamine Analogues as Novel Potent Mouse Trace Amine Associated Receptor 1 (mTAAR1) Agonists.
abstract: Trace amine associated receptor 1 (TAAR1) is a G protein coupled receptor (GPCR) expressed in brain and periphery activated by a wide spectrum of agonists that include, but are not limited to, trace amines (TAs), amphetamine-like psychostimulants, and endogenous thyronamines such as thyronamine (T0AM) and 3-iodothyronamine (T1AM). Such polypharmacology has made it challenging to understand the role and the biology of TAAR1. In an effort to understand the molecular basis of TAAR1 activation, we rationally designed and synthesized a small family of thyronamine derivatives. Among them, compounds 2 and 3 appeared to be a good mimic of the parent endogenous thyronamine, T0AM and T1AM, respectively, both in vitro and in vivo. Thus, these compounds offer suitable tools for studying the physiological roles of mouse TAAR1 and could represent the starting point for the development of more potent and selective TAAR1 ligands.
authors.affiliation: †Department of Pathology, University of Pisa, 56100 Pisa, Italy.
authors.forename: Grazia
authors.initials: G
authors.lastname: Chiellini
authors.affiliation: ‡Deptartment of Pharmacy, University of Pisa, via Bonanno 6, 56100 Pisa, Italy.
authors.forename: Giulia
authors.initials: G
authors.lastname: Nesi
authors.affiliation: ‡Deptartment of Pharmacy, University of Pisa, via Bonanno 6, 56100 Pisa, Italy.
authors.forename: Maria
authors.initials: M
authors.lastname: Digiacomo
authors.affiliation: ‡Deptartment of Pharmacy, University of Pisa, via Bonanno 6, 56100 Pisa, Italy.
authors.forename: Rossella
authors.initials: R
authors.lastname: Malvasi
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, 56100 Pisa, Italy.
authors.forename: Martina
authors.initials: M
authors.lastname: Sabatini
authors.affiliation: †Department of Pathology, University of Pisa, 56100 Pisa, Italy.
authors.forename: Sabina
authors.initials: S
authors.lastname: Frascarelli
authors.affiliation: ∥Department of NEUROFARBA, Section of Pharmacology, University of Florence, 50121 Firenze, 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: ‡Deptartment of Pharmacy, University of Pisa, via Bonanno 6, 56100 Pisa, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Macchia
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, 50121 Firenze, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Raimondi
authors.affiliation: †Department of Pathology, University of Pisa, 56100 Pisa, Italy.
authors.forename: Riccardo
authors.initials: R
authors.lastname: Zucchi
authors.affiliation: ‡Deptartment of Pharmacy, University of Pisa, via Bonanno 6, 56100 Pisa, Italy.
authors.forename: Simona
authors.initials: S
authors.lastname: Rapposelli
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D015195:Drug Design; D057809:HEK293 Cells; D006801:Humans; D008024:Ligands; D008297:Male; D051379:Mice; D008958:Models, Molecular; D008969:Molecular Sequence Data; D017208:Rats, Wistar; D043562:Receptors, G-Protein-Coupled / Q000819:agonists* / Q000737:chemistry / Q000378:metabolism*; D054852:Small Molecule Libraries / Q000737:chemistry / Q000494:pharmacology; D013970:Thyronines / Q000737:chemistry / Q000494:pharmacology; D000095383:Trace Amine-Associated Receptors
chemical_list: D001786:Blood Glucose; D008024:Ligands; D043562:Receptors, G-Protein-Coupled; D054852:Small Molecule Libraries; D013970:Thyronines; D000095383:Trace Amine-Associated Receptors; C004547:thyronamine