| Abstract
| - The acetylcholinesterase (AChE) inhibitory activity of a series of 13-amido derivatives of huprine Y, designedto enlarge the occupancy of the catalytic binding site by mimicking the piridone moiety present in (−)-huperzine A, has been assessed. Although both 13-formamido and 13-methanesulfonamido derivatives aremore potent human AChE inhibitors than tacrine and (−)-huperzine A, none of them equals the potency ofhuprine Y. Molecular modeling studies show that the two derivatives effectively trigger the Gly117-Gly118conformational flip induced upon binding of (−)-huperzine A, leading to a similar pattern of interactions asthat formed by the pyridone amido group of (−)-huperzine A. The detrimental effect on the binding affinityrelative to the 13-unsubstituted huprine could be ascribed to a sizable deformation cost associated with theligand-induced peptide flip. This finding can be interpreted as a mechanism selected by evolution to ensurethe preorganization of the functionally relevant oxyanion hole in the binding site of AChE, where residuesGly117 and Gly118 play a relevant role in mediating substrate recognition.
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