Heterodimeric Tacrine-Based Acetylcholinesterase Inhibitors: Investigating Ligand−Peripheral Site Interactions
| Autor: | E. S.-H. Chow, Paul R. Carlier, Yuan Ping Pang, Jing Liu, Yifan Han, J. El Yazal |
|---|---|
| Rok vydání: | 1999 |
| Předmět: |
Stereochemistry
In Vitro Techniques Crystallography X-Ray Ligands Chemical synthesis Structure-Activity Relationship chemistry.chemical_compound Drug Discovery medicine Animals Dimethylamine chemistry.chemical_classification biology Ligand Acetylcholinesterase Rats Enzyme chemistry Enzyme inhibitor Butyrylcholinesterase Drug Design Tacrine biology.protein Molecular Medicine Amine gas treating Cholinesterase Inhibitors Protein Binding medicine.drug |
| Zdroj: | Journal of Medicinal Chemistry. 42:4225-4231 |
| ISSN: | 1520-4804 0022-2623 |
| DOI: | 10.1021/jm990224w |
| Popis: | Dimeric acetylcholinesterase (AChE) inhibitors containing a single 9-amino-1,2,3,4-tetrahydroacridine (tacrine) unit were constructed in an effort to further delineate structural requirements for optimal binding to the AChE peripheral site. Basic amines of differing hydrophobicity were selected as peripheral site ligands, and in each case, improvements in inhibitory potency and selectivity were seen relative to tacrine itself. AChE IC50 values of the optimum dimers decrease significantly as the peripheral site ligand was permuted in the series ammonia > dimethylamine > 4-aminopyridine > 4-aminoquinoline > tacrine. Calculated desolvation free energies of the optimum dimers match the trend in IC50 values, suggesting the importance of ligand hydrophobicity for effective cation−π interaction with the peripheral site. |
| Databáze: | OpenAIRE |
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