Dolles, Dominik and Nimczick, Martin and Scheiner, Matthias and Ramler, Jacqueline and Stadtmueller, Patricia and Sawatzky, Edgar and Drakopoulos, Antonios and Sotriffer, Christoph and Wittmann, Hans-Joachim and Strasser, Andrea and Decker, Michael (2016) Aminobenzimidazoles and Structural Isomers as Templates for Dual-Acting Butyrylcholinesterase Inhibitors and hCB(2)R Ligands To Combat Neurodegenerative Disorders. CHEMMEDCHEM, 11 (12). pp. 1270-1283. ISSN 1860-7179, 1860-7187
Full text not available from this repository. (Request a copy)Abstract
A pharmacophore model for butyrylcholinesterase (BChE) inhibitors was applied to a human cannabinoid subtype 2 receptor (hCB(2)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 hCB(1) and AChE, respectively. Computational studies of the first-and second-generation lead structures by applying molecular dynamics (MD) on the active hCB(2)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. Dualacting 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.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | MOLECULAR MODELING INVESTIGATIONS; PROTEIN-COUPLED RECEPTORS; DESIGNED MULTIPLE LIGANDS; CANNABINOID CB1 RECEPTOR; ALZHEIMERS-DISEASE; BIOLOGICAL EVALUATION; IN-VITRO; BENZIMIDAZOLE DERIVATIVES; CRYSTAL-STRUCTURE; NATURAL-PRODUCTS; Alzheimer's disease; butyrylcholinesterase; cannabinoid receptor ligands; molecular dynamics; multitarget compounds |
| Subjects: | 500 Science > 540 Chemistry & allied sciences 600 Technology > 615 Pharmacy |
| Divisions: | Chemistry and Pharmacy > Institute of Pharmacy Chemistry and Pharmacy > Institute of Pharmacy > Pharmaceutical/Medicinal Chemistry II (Prof. Buschauer) |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 15 Mar 2019 11:25 |
| Last Modified: | 15 Mar 2019 11:25 |
| URI: | https://pred.uni-regensburg.de/id/eprint/3755 |
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