TY - JOUR
T1 - Evaluation of short-tether bis-THA AChE inhibitors. A further test of the dual binding site hypothesis
AU - Carlier, Paul R.
AU - Han, Yi Fan
AU - Chow, Ella S.H.
AU - Li, Crystal P.L.
AU - Wang, Hong
AU - Xuan Lieu, Thuy
AU - Sum Wong, Hau
AU - Pang, Yuan Ping
N1 - Funding Information:
The authors thank Dr. Bizeng Zhan for HPLC analyses, and the Research Grants Council (H. K.) for financial support of this work (Competitive Earmarked Research Grant HKUST 6156/97M).
PY - 1999/2
Y1 - 1999/2
N2 - 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. Copyright (C) 1999 Elsevier Science Ltd.
AB - 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. Copyright (C) 1999 Elsevier Science Ltd.
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U2 - 10.1016/S0968-0896(98)00213-2
DO - 10.1016/S0968-0896(98)00213-2
M3 - Article
C2 - 10218828
AN - SCOPUS:0033044911
SN - 0968-0896
VL - 7
SP - 351
EP - 357
JO - Bioorganic and Medicinal Chemistry
JF - Bioorganic and Medicinal Chemistry
IS - 2
ER -