Abstract
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 IC50values 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 IC50values, suggesting the importance of ligand hydrophobicity for effective cation-π interaction with the peripheral site.
Original language | English |
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Pages (from-to) | 4225-4231 |
Number of pages | 7 |
Journal | Journal of Medicinal Chemistry |
Volume | 42 |
Issue number | 20 |
DOIs | |
Publication status | Published - 7 Oct 1999 |
Externally published | Yes |
ASJC Scopus subject areas
- Molecular Medicine
- Drug Discovery