title: Further insights into the pharmacology of the human trace amine-associated receptors: discovery of novel ligands for TAAR1 by a virtual screening approach.
abstract: Trace Amine-Associated Receptor 1 (TAAR1) is a G protein-coupled receptor that is expressed in brain and periphery and responds to a class of compounds called trace amines, such as β-phenylethylamine (β-PEA), tyramine, tryptamine, octopamine. The receptor is known to have a very rich pharmacology and could be also activated by different classes of compounds, including dopaminergic, adrenergic and serotonergic ligands. It is expected that targeting hTAAR1 could provide a novel pharmacological approach for several human disorders, such as schizophrenia, depression, attention deficit hyperactivity disorder, Parkinson's disease and metabolic diseases. Only recently, a small number of selective hTAAR1 agonists (among which RO5166017 and T1 AM) and antagonist (EPPTB), have been reported in literature. With the aim to identify new molecular entities able to act as ligands for this target, we used an homology model for the hTAAR1 and performed a virtual screening procedure on an in-house database of compounds. A number of interesting molecules were selected and by testing them in an in vitro assay we found several agonists and one antagonist, with activities in the low micromolar range. These compounds could represent the starting point for the development of more potent and selective TAAR1 ligands.
authors.affiliation: Dipartimento di Farmacia, Università degli Studi di Genova, Viale Benedetto XV n. 3, Genova, 16132, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Cichero
authors.forename: Stefano
authors.initials: S
authors.lastname: Espinoza
authors.forename: Silvia
authors.initials: S
authors.lastname: Franchini
authors.forename: Sara
authors.initials: S
authors.lastname: Guariento
authors.forename: Livio
authors.initials: L
authors.lastname: Brasili
authors.forename: Raul R
authors.initials: RR
authors.lastname: Gainetdinov
authors.forename: Paola
authors.initials: P
authors.lastname: Fossa
mesh_terms: D001665:Binding Sites; D062126:Databases, Chemical; D004353:Drug Evaluation, Preclinical; D031541:Fluorescence Resonance Energy Transfer; D057809:HEK293 Cells; D006801:Humans; D008024:Ligands; D062105:Molecular Docking Simulation; D010080:Oxazoles / Q000737:chemistry / Q000378:metabolism; D010627:Phenethylamines / Q000737:chemistry / Q000378:metabolism; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D043562:Receptors, G-Protein-Coupled / Q000819:agonists* / Q000037:antagonists & inhibitors / Q000378:metabolism; D000095383:Trace Amine-Associated Receptors
chemical_list: D008024:Ligands; D010080:Oxazoles; D010627:Phenethylamines; D043562:Receptors, G-Protein-Coupled; D000095383:Trace Amine-Associated Receptors; C583451:RO5166017
keywords: G-protein coupled receptor; TAAR 1 receptor; virtual screening approach