Evaluation of short-tether bis-THA AChE inhibitors. A further test of the dual binding site hypothesis.
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.
Carlier
P R
PR
Department of Chemistry, Hong Kong University of Science and Technology, Clear Water Bay, Kowloon.
Han
Y F
YF
Chow
E S
ES
Li
C P
CP
Wang
H
H
Lieu
T X
TX
Wong
H S
HS
Pang
Y P
YP
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
D002800:Cholinesterase Inhibitors; C059724:9-hydroxylamine-1,2,3,4-tetrahydroacridine; D013619:Tacrine; D000110:Acetylcholinesterase; D002091:Butyrylcholinesterase