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Aminobenzimidazoles and Structural Isomers as Templates for Dual-Acting Butyrylcholinesterase Inhibitors and hCB2 R Ligands To Combat Neurodegenerative Disorders.
- Source :
-
ChemMedChem [ChemMedChem] 2016 Jun 20; Vol. 11 (12), pp. 1270-83. Date of Electronic Publication: 2015 Nov 09. - Publication Year :
- 2016
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Abstract
- 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.<br /> (© 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)
- Subjects :
- Amino Acid Sequence
Benzimidazoles metabolism
Benzimidazoles therapeutic use
Binding Sites
Butyrylcholinesterase metabolism
Cholinesterase Inhibitors chemical synthesis
Cholinesterase Inhibitors metabolism
Drug Design
Humans
Ligands
Molecular Docking Simulation
Molecular Dynamics Simulation
Molecular Sequence Data
Protein Structure, Tertiary
Receptor, Cannabinoid, CB1 chemistry
Receptor, Cannabinoid, CB1 metabolism
Receptor, Cannabinoid, CB2 metabolism
Sequence Alignment
Stereoisomerism
Structure-Activity Relationship
Benzimidazoles chemistry
Butyrylcholinesterase chemistry
Cholinesterase Inhibitors therapeutic use
Neurodegenerative Diseases drug therapy
Receptor, Cannabinoid, CB2 antagonists & inhibitors
Subjects
Details
- Language :
- English
- ISSN :
- 1860-7187
- Volume :
- 11
- Issue :
- 12
- Database :
- MEDLINE
- Journal :
- ChemMedChem
- Publication Type :
- Academic Journal
- Accession number :
- 26548365
- Full Text :
- https://doi.org/10.1002/cmdc.201500418