High Throughput Screening and Structure-Activity Relationship Study of Potential α2A-Adrenoceptor Agonists by LANCE™ 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. alpha(2)-adrenoceptors (alpha(2)-ARs) are one of the GPCRs and the stimulation of them could modulate many classical effects such as hypotension, bradycardia, etc.. Recently, alpha(2A)-AR is more and more important for its role in the therapeutic applications in central nervous system (CNS) diseases. High throughput screening of alpha(2A)-AR agonists was established by LANCE (TM) cAMP assay from a compound library of 80,000 small-molecule compounds to find out potential human alpha(2A)-adrenoceptor (alpha(2A)-AR) agonists that might have therapeutic effect in CNS diseases. From the preliminary and secondary screening, 37 compounds were identified as alpha(2A)-AR agonists, and six compounds among them presented more pronounced alpha(2A)-AR stimulating activity than guanfacine, a selective alpha(2A)-AR agonist. The study provided referred data for the development of potent alpha(2A)-AR agonists and suggested that the existence of the parent structure (1, 2, 4-benzothiadiazine 1, 1-dioxide) bodes well for pharmaceutical development of alpha(2A)-AR agonists.