Rational design, chemical synthesis and biological evaluation of novel biguanides exploring species-specificity responsiveness of TAAR1 agonists

The design of novel chemical classes acting towards several G-protein-coupled receptors (GPCRs) represents a leading strategy in drug discovery, aimed at deriving effective and safe candidates for further assessment. During the last years, TAAR1 arose as a promising druggable target in medicinal chemistry, being of interest in the treatment of several pathologies, such as neuropsychiatric disorders, type 2 diabetes and obesity. Nevertheless, the limited number of known potent and selective ligands and the species-specificity responsiveness exhibited by those derivatives nowadays available make the discovery of novel compounds a challenging task. Herein, we discuss the development of two quantitative-structure activity relationship (QSAR) models around the agonism ability experienced by different chemo-types toward murine and human TAAR1 (m/hTAAR1) with the aim at deciphering some clues involved in their species-specificity responsiveness. Qualitatively, these information were evaluated guiding for the synthesis of novel ligands, which proved to feature selective agonism ability with respect to the mTAAR1 and hTAAR1 orthologues. [Display omitted] •Biguanide-containing derivatives feature unselective agonism towards m/hTAAR1.•QSAR analyses allowed the rational design of novel biguanides.•Synthesis of novel piperazine-containing derivatives validated the QSAR results.•Two selective mTAAR1 agonists and one towards the human orthologue were identified.•Docking studies deepen the agonism ability and selectivity of the novel derivatives.