Currently, the only clinically effective treat
ment for Alzhei
mer’s disease (AD) is the use of acetylcholinesterase (AChE) inhibitors. These inhibitors have li
mited efficacy in that they only treat the sy
mpto
ms and not the disease itself. Additionally, they often have unpleasant side effects. Here we consider the viability of a single
molecule having the actions of both an AChE inhibitor and hista
mine H
3 receptor antagonist. Both hista
mine H
3 receptor antagonists and AChE inhibitors i
mprove and aug
ment cholinergic neurotrans
mission in the cortex. However, whereas an AChE inhibitor will i
mpart its effect everywhere, a hista
mine H
3 antagonist will raise acetylcholine levels
mostly in the brain as its
mode of action will pri
marily be on the central nervous syste
m. Therefore, the co
mbination of both activities in a single
molecule could be advantageous. Indeed, studies suggest an appropriate dual-acting co
mpound
may offer the desired therapeutic effect with fewer unpleasant side effects [
CNS Drugs 2004,
18, 827]. Further, recent studies
me="bbib2">m/science?_ob=ArticleURL&_udi=B6TF8-4RF459F-3&_user=10&_coverDate=03%2F15%2F2008&_rdoc=26&_fmt=full&_orig=browse&_srch=doc-info(%23toc%235220%232008%23999839993%23683917%23FLA%23display%23Volume)&_cdi=5220&_sort=d&_docanchor=&_ct=76&_acct=C000050221&_version=1&_urlVersion=0&_userid=10&md5=45c6c520359da335b9471f78784e9718#bib2">2 indicate the peripheral anionic site (PAS) of AChE interacts with the β-a
myloid (βA) peptide. Consequently, a
molecule capable of disrupting this interaction
may have a significant i
mpact on the production of or the aggregation of βA. This
may result in slowing down the progression of the disease rather than only treating the sy
mpto
ms as current therapies do. Here, we detail how the use of the available crystal structure infor
mation, phar
macophore
modeling and docking (auto
mated,
manual, classical, and QM/MM) lead to the identification of an AChE inhibitor–hista
mine H
3 receptor antagonist. Further, based on our
models we speculate that this dual-acting co
mpound
may interact with the PAS. Such a dual-acting co
mpound
may be able to affect the pathology of AD in addition to providing sy
mpto
matic relief.