Aminobenzimidazoles and Structural Isomers as Templates for Dual-Acting Butyrylcholinesterase Inhibitors and hCB2 R Ligands To Combat Neurodegenerative Disorders

A pharmacophore model for butyrylcholinesterase (BChE) inhibitors was applied to a human cannabinoid subtype 2 receptor (hCB2 R) agonist and verified it as a first-generation lead for respective dual-acting compounds. The design, synthesis, and pharmacological evaluation of various derivatives led t...

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Bibliographic Details
Published in:ChemMedChem 2016-06, Vol.11 (12), p.1270-1283
Main Authors: Dolles, Dominik, Nimczick, Martin, Scheiner, Matthias, Ramler, Jacqueline, Stadtmüller, Patricia, Sawatzky, Edgar, Drakopoulos, Antonios, Sotriffer, Christoph, Wittmann, Hans-Joachim, Strasser, Andrea, Decker, Michael
Format: Article
Language:English
Subjects:
Amino Acid Sequence
Benzimidazoles - chemistry
Benzimidazoles - metabolism
Benzimidazoles - therapeutic use
Binding Sites
Butyrylcholinesterase - chemistry
Butyrylcholinesterase - metabolism
Cholinesterase Inhibitors - chemical synthesis
Cholinesterase Inhibitors - metabolism
Cholinesterase Inhibitors - therapeutic use
Drug Design
Humans
Ligands
Molecular Docking Simulation
Molecular Dynamics Simulation
Molecular Sequence Data
Neurodegenerative Diseases - drug therapy
Protein Structure, Tertiary
Receptor, Cannabinoid, CB1 - chemistry
Receptor, Cannabinoid, CB1 - metabolism
Receptor, Cannabinoid, CB2 - antagonists & inhibitors
Receptor, Cannabinoid, CB2 - metabolism
Sequence Alignment
Stereoisomerism
Structure-Activity Relationship
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Summary:A pharmacophore model for butyrylcholinesterase (BChE) inhibitors was applied to a human cannabinoid subtype 2 receptor (hCB2 R) agonist and verified it as a first-generation lead for respective dual-acting compounds. The design, synthesis, and pharmacological evaluation of various derivatives led to the identification of aminobenzimidazoles as second-generation leads with micro- or sub-micromolar activities at both targets and excellent selectivity over hCB1 and AChE, respectively. Computational studies of the first- and second-generation lead structures by applying molecular dynamics (MD) on the active hCB2 R model, along with docking and MD on hBChE, has enabled an explanation of their binding profiles at the protein levels and opened the way for further optimization. Dual-acting compounds with "balanced" affinities and excellent selectivities could be obtained that represent leads for treatment of both cognitive and pathophysiological impairment occurring in neurodegenerative disorders.
ISSN:1860-7187
DOI:10.1002/CMDC.201500418