Discovery, cocrystallization and biological evaluation of novel piperidine derivatives as high affinity Ls-AChBP ligands possessing α7 nAChR activities
- Resource Type
- Authors
- Lu Zhou; Xicheng Yang; Wei Li; Qiong Xie; Liming Shao; Chenghan Zhang; Lulu Jiang; Mingcheng Yu; Li Xiao; Guanxing Pan; Jian Shen; Linqian Yu; Hao Chen; Yu-rong Yan; Yilin Zheng; Wanwan Jia; Haihua Yu
- Source
- European Journal of Medicinal Chemistry. 160:37-48
- Subject
- Models, Molecular
0301 basic medicine
alpha7 Nicotinic Acetylcholine Receptor
Stereochemistry
Crystallography, X-Ray
Ligands
Structure-Activity Relationship
03 medical and health sciences
chemistry.chemical_compound
Piperidines
Drug Discovery
Pyridine
Animals
Humans
Nicotinic Agonists
Lymnaea
Biological evaluation
Pharmacology
Halogen bond
Dose-Response Relationship, Drug
Molecular Structure
Organic Chemistry
General Medicine
030104 developmental biology
Binding conformation
chemistry
Docking (molecular)
Piperidine
Enantiomer
Carrier Proteins
α7 nachr
- Language
- ISSN
- 0223-5234
A series of novel pyridine-substituted piperidine derivatives were discovered as low nanomolar Ls-AChBP ligands with α7 nAChR partial agonism or antagonism activities. A high-resolution antagonist-bound Ls-AChBP complex was successfully resolved with a classic Loop C opening phenomenon and unique sulfur-π interactions which deviated from our previous docking mode to a large extent. With the knowledge of the co-complex, 27 novel piperidine derivatives were designed and synthesized. The structure-activity relationships (SARs) of the aromatic and pyridine regions were well established and binding modes were illustrated with the help of molecular docking which indicated that interactions with Trp 143 and the “water bridge” are essential for the high binding affinities. Halogen bonding as well as the space around 5′- or 6′- position of the pyridine ring was also proposed to influence the binding conformation of the compounds. Notably, two enantiomers of compound 2 showed opposite functions toward α7 nAChR and compound (S)-2 showed sub-nanomolar affinity (Ki = 0.86 nM) on Ls-AChBP and partial agonism (pEC50 = 4.69 ± 0.11,Emax = 36.1%) on α7 nAChR with reasonable pharmacokinetics (PK) properties and fine ability of blood-brain-barrier (BBB) penetration. This study provided promising hits to develop candidates targeting nAChR-related CNS diseases.