title: Design and Synthesis of Nicotinic Acetylcholine Receptor Antagonists and their Effect on Cognitive Impairment.
abstract: 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 Kd values of 260 and 10 nm, respectively. Functional assays on isolated cell lines containing ligand-gated ion channels revealed that QN1 and BZ1 are a4b2-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.
authors.affiliation: Center of Excellence for Innovation in Drug Design and Discovery, Faculty of Pharmacy, Mahidol University, 447 Sri-Ayudya Road, Bangkok, 10400, Thailand.
authors.forename: Pattaporn
authors.initials: P
authors.lastname: Jaikhan
authors.affiliation: Department of Pharmaceutical Chemistry, Faculty of Pharmaceutical Science, KhonKaen University, KhonKaen, 4000, Thailand.
authors.forename: Chantana
authors.initials: C
authors.lastname: Boonyarat
authors.affiliation: Center of Excellence for Innovation in Drug Design and Discovery, Faculty of Pharmacy, Mahidol University, 447 Sri-Ayudya Road, Bangkok, 10400, Thailand.|Department of Pharmacology, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA, 92093-0657, USA.
authors.forename: Kuntarat
authors.initials: K
authors.lastname: Arunrungvichian
authors.affiliation: Department of Pharmacology, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA, 92093-0657, USA.
authors.forename: Palmer
authors.initials: P
authors.lastname: Taylor
authors.affiliation: Center of Excellence for Innovation in Drug Design and Discovery, Faculty of Pharmacy, Mahidol University, 447 Sri-Ayudya Road, Bangkok, 10400, Thailand.
authors.forename: Opa
authors.initials: O
authors.lastname: Vajragupta
mesh_terms: D003072:Cognition Disorders / Q000188:drug therapy*; D015195:Drug Design; D009682:Magnetic Resonance Spectroscopy; D062105:Molecular Docking Simulation; D018733:Nicotinic Antagonists / Q000138:chemical synthesis* / Q000494:pharmacology* / Q000627:therapeutic use; D011978:Receptors, Nicotinic / Q000187:drug effects*; D021241:Spectrometry, Mass, Electrospray Ionization
chemical_list: D018733:Nicotinic Antagonists; D011978:Receptors, Nicotinic
keywords: acetylcholine-binding protein; competitive antagonists; nicotinic acetylcholine receptors; non-competitive; α4β2 nicotinic acetylcholine receptor antagonists