title: Discovery, synthesis, biological evaluation and structure-based optimization of novel piperidine derivatives as acetylcholine-binding protein ligands.
abstract: The homomeric α7 nicotinic receptor (α7 nAChR) is widely expressed in the human brain that could be activated to suppress neuroinflammation, oxidative stress and neuropathic pain. Consequently, a number of α7 nAChR agonists have entered clinical trials as anti-Alzheimer's or anti-psychotic therapies. However, high-resolution crystal structure of the full-length α7 receptor is thus far unavailable. Since acetylcholine-binding protein (AChBP) from Lymnaea stagnalis is most closely related to the α-subunit of nAChRs, it has been used as a template for the N-terminal domain of α-subunit of nAChR to study the molecular recognition process of nAChR-ligand interactions, and to identify ligands with potential nAChR-like activities.Here we report the discovery and optimization of novel acetylcholine-binding protein ligands through screening, structure-activity relationships and structure-based design. We manually screened in-house CNS-biased compound library in vitro and identified compound 1, a piperidine derivative, as an initial hit with moderate binding affinity against AChBP (17.2% inhibition at 100 nmol/L). During the 1st round of optimization, with compound 2 (21.5% inhibition at 100 nmol/L) as the starting point, 13 piperidine derivatives with different aryl substitutions were synthesized and assayed in vitro. No apparent correlation was demonstrated between the binding affinities and the steric or electrostatic effects of aryl substitutions for most compounds, but compound 14 showed a higher affinity (Ki=105.6 nmol/L) than nicotine (Ki=777 nmol/L). During the 2nd round of optimization, we performed molecular modeling of the putative complex of compound 14 with AChBP, and compared it with the epibatidine-AChBP complex. The results suggested that a different piperidinyl substitution might confer a better fit for epibatidine as the reference compound. Thus, compound 15 was designed and identified as a highly affinitive acetylcholine-binding protein ligand. In this study, through two rounds of optimization, compound 15 (Ki=2.8 nmol/L) has been identified as a novel, piperidine-based acetylcholine-binding protein ligand with a high affinity.
authors.affiliation: Department of Medicinal Chemistry, School of Pharmacy, Fudan University, Shanghai 201203, China.
authors.forename: Jian
authors.initials: J
authors.lastname: Shen
authors.affiliation: Department of Medicinal Chemistry, School of Pharmacy, Fudan University, Shanghai 201203, China.
authors.forename: Xi-Cheng
authors.initials: XC
authors.lastname: Yang
authors.affiliation: Department of Medicinal Chemistry, School of Pharmacy, Fudan University, Shanghai 201203, China.
authors.forename: Ming-Cheng
authors.initials: MC
authors.lastname: Yu
authors.affiliation: Department of Medicinal Chemistry, School of Pharmacy, Fudan University, Shanghai 201203, China.
authors.forename: Li
authors.initials: L
authors.lastname: Xiao
authors.affiliation: Department of Medicinal Chemistry, School of Pharmacy, Fudan University, Shanghai 201203, China.
authors.forename: Xun-Jie
authors.initials: XJ
authors.lastname: Zhang
authors.affiliation: Department of Medicinal Chemistry, School of Pharmacy, Fudan University, Shanghai 201203, China.
authors.forename: Hui-Jiao
authors.initials: HJ
authors.lastname: Sun
authors.affiliation: Department of Medicinal Chemistry, School of Pharmacy, Fudan University, Shanghai 201203, China.
authors.forename: Hao
authors.initials: H
authors.lastname: Chen
authors.affiliation: Department of Medicinal Chemistry, School of Pharmacy, Fudan University, Shanghai 201203, China.
authors.forename: Guan-Xin
authors.initials: GX
authors.lastname: Pan
authors.affiliation: Department of Medicinal Chemistry, School of Pharmacy, Fudan University, Shanghai 201203, China.
authors.forename: Yu-Rong
authors.initials: YR
authors.lastname: Yan
authors.affiliation: Department of Medicinal Chemistry, School of Pharmacy, Fudan University, Shanghai 201203, China.
authors.forename: Si-Chen
authors.initials: SC
authors.lastname: Wang
authors.affiliation: Department of Medicinal Chemistry, School of Pharmacy, Fudan University, Shanghai 201203, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Li
authors.affiliation: Department of Medicinal Chemistry, School of Pharmacy, Fudan University, Shanghai 201203, China.
authors.forename: Lu
authors.initials: L
authors.lastname: Zhou
authors.affiliation: Department of Medicinal Chemistry, School of Pharmacy, Fudan University, Shanghai 201203, China.
authors.forename: Qiong
authors.initials: Q
authors.lastname: Xie
authors.affiliation: Department of Medicinal Chemistry, School of Pharmacy, Fudan University, Shanghai 201203, China.
authors.forename: Lin-Qian
authors.initials: LQ
authors.lastname: Yu
authors.affiliation: Department of Medicinal Chemistry, School of Pharmacy, Fudan University, Shanghai 201203, China.
authors.forename: Yong-Hui
authors.initials: YH
authors.lastname: Wang
authors.affiliation: Department of Medicinal Chemistry, School of Pharmacy, Fudan University, Shanghai 201203, China.
authors.forename: Li-Ming
authors.initials: LM
authors.lastname: Shao
mesh_terms: D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology; D002352:Carrier Proteins / Q000737:chemistry* / Q000378:metabolism; D015195:Drug Design; D008024:Ligands; D008958:Models, Molecular; D062105:Molecular Docking Simulation; D009538:Nicotine / Q000494:pharmacology; D010880:Piperidines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology; D011869:Radioligand Assay; D013329:Structure-Activity Relationship
chemical_list: C428944:AChBP protein, Lymnaea; D019086:Bridged Bicyclo Compounds, Heterocyclic; D002352:Carrier Proteins; D008024:Ligands; D010880:Piperidines; D011725:Pyridines; D009538:Nicotine; C082748:epibatidine