title: Heterodimeric tacrine-based acetylcholinesterase inhibitors: investigating ligand-peripheral site interactions.
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 IC(50) 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 IC(50) values, suggesting the importance of ligand hydrophobicity for effective cation-pi interaction with the peripheral site.
authors.affiliation: Department of Chemistry, Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong. chpaul@ust.hk
authors.forename: P R
authors.initials: PR
authors.lastname: Carlier
authors.forename: E S
authors.initials: ES
authors.lastname: Chow
authors.forename: Y
authors.initials: Y
authors.lastname: Han
authors.forename: J
authors.initials: J
authors.lastname: Liu
authors.forename: J
authors.initials: J
authors.lastname: El Yazal
authors.forename: Y P
authors.initials: YP
authors.lastname: Pang
mesh_terms: D000110:Acetylcholinesterase / Q000378:metabolism; D000818:Animals; D002091:Butyrylcholinesterase / Q000378:metabolism; D002800:Cholinesterase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D018360:Crystallography, X-Ray; D015195:Drug Design; D066298:In Vitro Techniques; D008024:Ligands; D011485:Protein Binding; D051381:Rats; D013329:Structure-Activity Relationship; D013619:Tacrine / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
chemical_list: D002800:Cholinesterase Inhibitors; D008024:Ligands; D013619:Tacrine; D000110:Acetylcholinesterase; D002091:Butyrylcholinesterase