title: Evaluation of short-tether bis-THA AChE inhibitors. A further test of the dual binding site hypothesis.
abstract: To provide a further test of the dual binding site hypothesis proposed for acetylcholinesterase (AChE) inhibitor heptylene-linked bis-(9-amino-1,2,3,4-tetrahydroacridine) A7A, short-tether (ethylene hexylene) homologs A2A-A6A were prepared. En route to these compounds, convenient and scaleable syntheses of useful pharmaceutical intermediate 9-chloro-1.2,3,4-tetrahydroacridine 3 and A7A were developed. AChE and butyrylcholinesterase (BChE) inhibition assays of A2A-A10A confirm that a seven methylene tether (A7A) optimizes AChE inhibition potency and AChE/BChE selectivity. Finally, these studies indicate that simultaneous binding of alkylene-linked 9-amino-1,2,3,4-tetrahydroacridine dimers to the catalytic and peripheral sites of AChE is possible with a tether length as short as 5 methylenes.
authors.affiliation: Department of Chemistry, Hong Kong University of Science and Technology, Clear Water Bay, Kowloon.
authors.forename: P R
authors.initials: PR
authors.lastname: Carlier
authors.forename: Y F
authors.initials: YF
authors.lastname: Han
authors.forename: E S
authors.initials: ES
authors.lastname: Chow
authors.forename: C P
authors.initials: CP
authors.lastname: Li
authors.forename: H
authors.initials: H
authors.lastname: Wang
authors.forename: T X
authors.initials: TX
authors.lastname: Lieu
authors.forename: H S
authors.initials: HS
authors.lastname: Wong
authors.forename: Y P
authors.initials: YP
authors.lastname: Pang
mesh_terms: D000110:Acetylcholinesterase / Q000097:blood / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000378:metabolism; D002091:Butyrylcholinesterase / Q000097:blood / Q000378:metabolism; D002800:Cholinesterase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry*; D020128:Inhibitory Concentration 50; D013058:Mass Spectrometry; D008956:Models, Chemical; D011485:Protein Binding; D051381:Rats; D013619:Tacrine / Q000031:analogs & derivatives* / Q000737:chemistry; D013696:Temperature
chemical_list: D002800:Cholinesterase Inhibitors; C059724:9-hydroxylamine-1,2,3,4-tetrahydroacridine; D013619:Tacrine; D000110:Acetylcholinesterase; D002091:Butyrylcholinesterase