Design, Synthesis, Biological Properties, and Molecular Modeling Investigations of Novel Tacrine Derivatives with a Combination of Acetylcholinesterase Inhibition and Cannabinoid CB1 Receptor Antagonism
| Autor: | Peter C Verveer, Bob Stork, Hein K. A. C. Coolen, Alice J.M. Borst, Josephus H. M. Lange, Martina A.W. van der Neut, Chris G. Kruse |
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| Rok vydání: | 2010 |
| Předmět: |
Models
Molecular Cannabinoid receptor Protein Conformation Stereochemistry medicine.medical_treatment CHO Cells Crystallography X-Ray Kidney Receptor Cannabinoid CB2 Structure-Activity Relationship chemistry.chemical_compound Cricetulus Receptor Cannabinoid CB1 Cricetinae Drug Discovery medicine Cannabinoid receptor type 2 Animals Humans Cells Cultured Molecular Structure biology Cannabinoids musculoskeletal neural and ocular physiology food and beverages Biological activity Acetylcholinesterase nervous system chemistry Biochemistry Enzyme inhibitor Drug Design Tacrine biology.protein Molecular Medicine lipids (amino acids peptides and proteins) Cholinesterase Inhibitors Cannabinoid Pharmacophore psychological phenomena and processes medicine.drug |
| Zdroj: | Journal of Medicinal Chemistry. 53:1338-1346 |
| ISSN: | 1520-4804 0022-2623 |
| Popis: | Pyrazolines 7-10 were designed as novel CB(1) receptor antagonists, which exhibited improved turbidimetric aqueous solubilities. On the basis of their extended CB(1) antagonist pharmacophore, hybrid molecules exhibiting cannabinoid CB(1) receptor antagonistic as well as acetylcholinesterase (AChE) inhibiting activities were designed. The target compounds 12, 13, 20, and 21 are based on 1 (tacrine) as the AChE inhibitor (AChEI) pharmacophore and two different CB(1) antagonistic pharmacophores. The imidazole-based 20 showed high CB(1) receptor affinity (48 nM) in combination with high CB(1)/CB(2) receptor subtype selectivity (20-fold) and elicited equipotent AChE inhibitory activity as 1. Molecular modeling studies revealed the presence of a binding pocket in the AChE enzyme which nicely accommodates the CB(1) pharmacophores of the target compounds 12, 13, 20, and 21. |
| Databáze: | OpenAIRE |
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