LAUSR

Nowadays, compounds targeting G-protein-coupled receptors (GPCRs) represent a large amount of clinically relevant drugs, depicting a leading role in the drug discovery panorama. Trace amine-associated receptors (TAARs) belong to the family of GPCRs, whose first identified member TAAR1 was cloned and first investigated at the beginning of the twentyfirst century by different research groups, independently [1,2]. Bunzow and colleagues discussed the discovery of this GPCR family in rodents as activated by the so-called trace amines (TAs), such as 3-iodo-thyronamine (T1AM), β-phenylethylamine (β-PEA), octopamine, and tryptamine. Moreover, they reported responsiveness of rodent TAAR1 (rTAAR1) to psychostimulant, amphetamine (AMPH), methamphetamine (METH), and ergoline derivatives, due to the structural similarity with some classical neurotransmitters [1]. Concurrent studies by Borowsky and coworkers revealed and confirmed the presence of TAAR1 receptors in rodent as well as in human tissues [2], suggesting for the first time a role played by TAs also in mammalians [3–6]. The discovery of TAAR1 receptors allowed to better investigate TAs not only as (secondary) neuromodulators but also as neurotransmitters and to draw new ways for further insights around the potential involvement of these GPCRs in numerous diseases. Thus, this receptor family recently arose as a promising druggable target in medicinal chemistry, since related agonists proved to be active in the treatment of several pathologies, such as neuropsychiatric disorders, type 2 diabetes, and obesity [7]. Up to now, relevant efforts in the search of novel agonists were performed, aimed at designing more potent and selective ligands devoid of any side efficacy toward other highly related GPCR (e.g. adrenergic and serotoninergic systems). This search was managed focusing on responsiveness featured by different chemo-types toward rTAAR1 and human TAAR1 (hTAAR1), in order to explore potency and species-specificity preferences. Nevertheless, the limited number of the so far available ligands, which efficiently target the human ortholog, makes the discovery of novel compounds still a challenging task.