| Abstract
| - Recently, alkylene-linked heterodimers of tacrine (1) and 5-amino-5,6,7,8-tetrahydroquinolinone(2, hupyridone) were shown to exhibit higher acetylcholinesterase (AChE) inhibition than either monomeric1 or 2. Such inhibitors are potential drug candidates for ameliorating the cognitive decrements in earlyAlzheimer patients. In an attempt to understand the inhibition mechanism of one such dimer, (RS)-(±)-N-9-(1,2,3,4-tetrahydroacridinyl)-N‘-5-[5,6,7,8-tetrahydro-2‘(1‘H)-quinolinonyl]-1,10-diaminodecane [(RS)-(±)-3] bisoxalate, the racemate was soaked in trigonal Torpedocalifornica AChE (TcAChE) crystals, and theX-ray structure of the resulting complex was solved to 2.30 Å resolution. Its structure revealed the 1 unitbound to the “anionic” subsite of the active site, near the bottom of the active-site gorge, as seen for the1/TcAChE complex. Interestingly, only the (R)-enantiomer of the 2 unit was seen in the peripheral “anionic”site (PAS) at the top of the gorge, and was hydrogen-bonded to the side chains of residues belonging toan adjacent, symmetry-related AChE molecule covering the gorge entrance. When the same racematewas soaked in orthorhombic crystals of TcAChE, in which the entrance to the gorge is more exposed, thecrystal structure of the corresponding complex revealed no substantial enantiomeric selectivity. Thisobservation suggests that the apparent enantiomeric selectivity of trigonal crystals of TcAChE for (R)-3 ismainly due to crystal packing, resulting in preferential binding of one enantiomeric inhibitor both to its “host”enzyme and to its neighbor in the asymmetric unit, rather than to steric constraints imposed by the geometryof the active-site gorge.
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