High Throughput Screening and Structure-Activity Relationship Study of Potential α2A-Adrenoceptor Agonists by LANCETM cAMP Assay

G protein-coupled receptors (GPCRs) are signaling molecules with a wide variety of skills. Members of this large family of membrane protein have been shown to regulate the activities of the different signaling pathways of the ligand specific manner. α2–adrenoceptors (α2-ARs) are one of the GPCRs and the stimulation of them could modulate many classical effects such as hypotension, bradycardia, etc.. Recently, α2A-AR is more and more important for its role in the therapeutic applications in central nervous system (CNS) diseases. High throughput screening of α2A-AR agonists was established by LANCETM cAMP assay from a compound library of 80,000 small-molecule compounds to find out potential human α2A-adrenoceptor (α2A-AR) agonists that might have therapeutic effect in CNS diseases. From the preliminary and secondary screening, 37 compounds were identified as α2AAR agonists, and six compounds among them presented more pronounced α2A-AR stimulating activity than guanfacine, a selective α2A-AR agonist. The study provided referred data for the development of potent α2A-AR agonists and suggested that the existence of the parent structure (1, 2, 4-benzothiadiazine 1, 1-dioxide) bodes well for pharmaceutical development of α2A-AR agonists.