Synthesis of novel phenserine-based-selective inhibitors of butyrylcholinesterase for Alzheimer's disease

Four novel analogues (8-11) of cymserine (2) were synthesized by methods si milar to those recently developed for the total syntheses of N-8-norphenser ine (Yu, Q. S.; et al. J. Med. Chem. 1997, 40, 2895-2901) and N-1,N-8-bisno rphenserine (Yu, Q. S.; et al. J. Med. Chem. 1998, 41, 2371-2379). As our s tructure-activity studies predicted, these compounds are highly potent and selective inhibitors of human butyryleholinesterase (BChE) and will test th e novel hypothesis that BChE inhibitors are useful in the treatment of Alzh eimer's disease. In a similar manner, the same modifications that provided BChE selectivity were applied to the acetylcholinesterase (AChE)-selective inhibitor, tolserine (5), to provide the novel tolserine analogues 12-15. A s predicted, these modifications altered the AChE-selective action of tolse rine (5) to favor a lack of cholinesterase enzyme subtype selectivity.