A new generation of β-adrenergic receptor (β-ARs) ligands: rational design, synthesis, and pharmacological evaluation

β-adrenergic receptors (β-ARs), comprising of three subtypes (β1/β2/β3), belong to G-protein-coupled receptors and mediate a wide range of catecholamine-induced physiological responses. Recent reports demonstrated that β-ARs, and in particular β2- and β3-AR, are over-expressed in various types of cancer and that β-ARs signaling is involved in boosting the malignant potential of tumor cells by enhancing the invasiveness of cancer cells, thus opening a new area of research in oncology called ‘Neurobiology of cancer’. Drug discovery for β-ARs is complicated by the plasticity of β-ARs, that affects receptor subtype selectivity, and the ligand-directed signaling, namely the ability of β-AR ligands to direct the signaling toward one pathway or another according to the state (active/inactive) and the conformation of the β-AR they bind. In this regard, this PhD project aims to identify new molecular entities that enable in-depth exploration of the ligand space around the previously reported ligands, leading to insights into their structure−activity relationships.4 Providing structural diversity can help to correlate, at the atomic level, the chemical structures and the activity toward β-ARs. To gain this goal a systematic study is proposed. It consists of i) the rational structure-based design and the stereoselective synthesis of novel potential β-AR ligands; ii) evaluation of the pharmacological profile of the synthesized compounds; iii) docking calculation using a novel homology model for the β-ARs.