Insights into the structure and pharmacology of Trace Amine-Associated Receptor 1 (TAAR1), a new target for medicinal chemistry

Trace amines (TAs), such as b-phenylethylamine (b-PEA), tyramine, 3-iodothyronamine (T1AM), octopamine, tryptamine and synephrine, are found at low levels in multiple tissues in the periphery and brain of mammals but their physiological functions remain enigmatic. A recent discovery of a family of rhodopsin-like G protein-coupled receptors (GPCRs), defined as Trace Amine-Associated Receptors (TAARs), has provided an opportunity to explore the roles of TAs and their receptors in physiology and disease. The human TAAR family consists of six genes and three pseudogenes and characterized by location on a single chromosome, high overall sequence homology to monoamine receptors, and the presence of a TAAR-specific peptide fingerprint motif with the seventh transmembrane domain that is not found in all other known GPCRs. It is believed that the TAAR family most likely evolved from a common ancestor gene sharing closest similarity to the human gene encoding serotonin 5-HT4 receptor via a series of gene duplication events [1]. The most studied Trace Amine-Associated Receptor 1 (TAAR1) signals via the Gs protein/adenylyl cyclase system and could be activated not only by TAs, but also by amphetamine derivatives, monoamine metabolites, iodothyronamines, ergolines as well as certain adrenergic and serotonergic drugs [2, 3]. Until recently, the lack of selective ligands has rendered a challenging task the exploration of TAAR1 biological functions. Only in 2010-2011, Hoener and co-workers have reported the identification of first selective TAAR1 ligands [4] with selective TAAR1 agonist RO5166017 being much more potent than the trace amine -PEA. TAAR1 is expressed in several brain regions. Accumulating evidence indicates that TAAR1 is involved in the modulation of dopaminergic and serotonergic systems, making this receptor as a promising novel target for drug discovery to manage monoaminergic disorders such as schizophrenia, depression, attention deficit hyperactivity disorders (ADHD) and Parkinson’s disease [5]. Up to now, experimental data highlighting the hTAAR1 key residues responsible for ligand recognition are not available. The aim of this study was to perform an “in silico” investigation focused to explore which different amino acid residues could be involved in the binding of hTAAR1 ligands, so as to have a useful tool for the virtual identification of new chemical entities acting on this protein.