Dimerization of an Inactive Fragment of Huperzine A Produces a Drug with Twice the Potency of the Natural Product

Abstract

Simultaneous binding to the catalytic and peripheral sites of acetylcholinesterase (AChE) is invoked to explain why the new drug (S,S)-(−)-3, in which two aminoquinolinone units are linked by a dodecamethylene tether, is more than twice as potent as the natural product huperzine A (−)-1 in the inhibition of AChE. In contrast aminoquinolinone (±)-2, which retains much of the functionality of (−)-1, inhibits AChE only very weakly.