Introduction: The greater interest in TAAR1-mediated potential for the treatment of different pathologies, especially those related to CNS disorders, has given a considerable boost to the search for developing TAAR1-selective small molecules.Areas covered: During the last decade, the medicinal chemistry efforts have allowed the yield of various chemotypes to be properly dressed toward TAAR1 receptor. The more relevant chemical features and structure-activity relationship studies on the TAAR1 ligands will be discussed in order to guide future drug discovery investigations.Expert opinion: The discovery of TAAR receptors has allowed better investigation of the role played by TAs, not only as secondary neuromodulators, but also as neurotransmitters, even if it should still be completely clarified. This has drawn new ways for further insights around the TAAR1 involvement in numerous diseases. Despite this, the limited number of promising ligands targeting hTAAR1 orthologue makes the discovery of novel compounds still a challenging task. Relevant efforts have to be focused on safe ligands, devoid of any side-efficacy toward other highly related GPCR (monoaminergic systems). Moreover, species-specificity preferences experienced by numerous compounds so far investigated, based on rodent models and translated to the human environment, turn in a critical bottleneck in drug discovery.
Keywords: Medicinal chemistry; TAAR1 agonists; TAAR1 chemotypes; hTAAR1; m/rTAAR1.