Pattaporn JaikhanChantana BoonyaratKuntarat ArunrungvichianPalmer TaylorOpa VajraguptaMahidol UniversityKhon Kaen UniversityUniversity of California, San Diego2018-12-112019-03-142018-12-112019-03-142016-01-01Chemical Biology and Drug Design. Vol.87, No.1 (2016), 39-5617470285174702772-s2.0-84955697524https://repository.li.mahidol.ac.th/handle/20.500.14594/43196© 2015 John Wiley & Sons A/S. Structure modification of a lead compound (NSC13378) was accomplished in the present work by an in silico target-based design aimed at ligands acting on the nicotinic acetylcholine receptor (nAChR) for neurodegenerative diseases. A 187-compound focused library derived from the scaffold of the lead compound was screened against acetylcholine-binding proteins (AChBPs). Six compounds were identified and synthesized for binding and biological evaluations. Five compounds were found to bind with AChBPs. Among these compounds, QN1 and BZ1 showed the highest affinity binding with AChBP, with Kdvalues of 260 and 10 nm, respectively. Functional assays on isolated cell lines containing ligand-gated ion channels revealed that QN1 and BZ1 are α4β2-nAChR antagonists. QN1 and BZ1 significantly alleviated the memory impairment caused by the muscarinic cholinergic antagonist scopolamine (p < 0.05) in mice. Our findings demonstrate the potential of nAChR antagonists in drug development for cognitive impairments.Mahidol UniversityBiochemistry, Genetics and Molecular BiologyArticleSCOPUS10.1111/cbdd.12627