Darras, Fouad H. and Pockes, Steffen and Huang, Guozhenz and Wehle, Sarah and Strasser, Andrea and Wittmann, Hans-Joachim and Nimczick, Martin and Sotriffer, Christoph A. and Decker, Michael (2014) Synthesis, Biological Evaluation, and Computational Studies of Tri- and Tetracyclic Nitrogen-Bridgehead Compounds as Potent Dual-Acting AChE Inhibitors and hH(3) Receptor Antagonists. ACS CHEMICAL NEUROSCIENCE, 5 (3). pp. 225-242. ISSN 1948-7193,
Full text not available from this repository. (Request a copy)Abstract
Combination of AChE inhibiting and histamine H-3 receptor antagonizing properties in a single molecule might show synergistic effects to improve cognitive deficits in Alzheimer's disease, since both pharmacological actions are able to enhance cholinergic neurotransmission in the cortex. However, whereas AChE inhibitors prevent hydrolysis of acetylcholine also peripherally, histamine H-3 antagonists will raise acetylcholine levels mostly in the brain due to predominant occurrence of the receptor in the central nervous system. In this work, we designed and synthesized two novel classes of tri- and tetracyclic nitrogen-bridgehead compounds acting as dual AChE inhibitors and histamine H-3 antagonists by combining the nitrogen-bridgehead moiety of novel AChE inhibitors with a second N-basic fragment based on the piperidinylpropoxy pharmacophore with different spacer lengths. Intensive structure activity relationships (SARs) with regard to both biological targets led to compound 41 which showed balanced affinities as hAChE inhibitor with IC50 = 33.9 nM, and hH(3)R antagonism with K-i = 76.2 nM with greater than 200-fold selectivity over the other histamine receptor subtypes. Molecular docking studies were performed to explain the potent AChE inhibition of the target compounds and molecular dynamics studies to explain high affinity at the hH(3)R
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | HISTAMINE H-3 RECEPTOR; GENETIC ALGORITHM; LIGAND DOCKING; ACETYLCHOLINESTERASE; TACRINE; IDENTIFICATION; EPIDEMIOLOGY; SELECTIVITY; AGONIST; COMPLEX; Acetylcholinesterase inhibitors; histamine H-3 antagonists; Alzheimer's disease; docking; MD simulation |
| Subjects: | 600 Technology > 615 Pharmacy |
| Divisions: | Chemistry and Pharmacy > Institute of Pharmacy > Pharmaceutical/Medicinal Chemistry I (Prof. Elz) Chemistry and Pharmacy > Institute of Pharmacy > Pharmaceutical/Medicinal Chemistry II (Prof. Buschauer) |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 19 Nov 2019 14:50 |
| Last Modified: | 19 Nov 2019 14:50 |
| URI: | https://pred.uni-regensburg.de/id/eprint/10562 |
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