Wyman and Macartney
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CHART 1. Cucurbit[7]uril
We have recently observed that cholines, including acet-
ylcholine, and their trialkylphosphonium analogues form
stable 1:1 host-guest complexes with cucurbit[7]uril in aqu-
eous solution.10 The cucurbit[n]urils (CB[n], n=5-8, 10) are
a family of macrocyclic host molecules comprising n glyco-
luril units bridged by 2n methylene groups (Chart 1).11 Their
hydrophobic cavities and constrictive polar portals, lined
with n ureido carbonyl groups, allow for the formation of
exceedingly stable host-guest complexes in aqueous solu-
tion, particularly cucurbit[7]uril with cationic organic and
organometallic guests. With the 1,10-bis(trimethylammonio-
methyl)ferrocene guest, for example, a host-guest stability
constant of KCB[7]=3ꢀ1015 M-1 with CB[7] (Chart 1) has
been determined from serial competitive binding studies.12
The inclusion of a variety of cationic guests has been shown
to significantly affect their chemical properties such as pKa
values,13 chemical and photolytic stabilities,14 and UV-vis
absorption and emission spectra.15 Nau and co-workers
have devised enzyme assays based on fluorescent indicator
displacement CB[7] detection of enzymatic substrates or
products.16 Mohanty and co-workers have found that the
fluorescent dye thioflavin T, used extensively to probe the
presence of amyloid fibrils, forms 1:1 and 2:1 host-guest
complexes with cucurbit[7]uril, with binding constants
of ∼105 and ∼103 M-1, respectively.17 Interestingly, this
cationic benzothiazonium dye molecule also binds to the
peripheral site of TcAChE and can be used to probe sub-
strate interactions at the catalytic site in the gorge.18
antagonist memantine (1,3-dimethyladamantamine) is used
alone or in combination with one of the AChE inhibitors.
The AChE inhibitors and memantine have been shown to
slow the progression of the disease through acetylcholine
regulation, as well as by providing anti-inflammatory bene-
fits and increased antioxidant production.4,5
The inhibition of AChE can be accomplished irreversibly
(organophosphates form a strong covalent bond with the
serine residue in the catalytic triad), pseudoirreversibly
(using carbamates, as the carbamylated serine is slowly
hydrolyzed to regenerate the active enzyme), or reversibly
(transient noncovalent binding through electrostatic inter-
actions with the active and/or peripheral sites), depending on
the nature of the interaction of the inhibitor with the enzyme
site.6 The reversible inhibitors may be classified as (a) active-
site inhibitors directed toward the catalytic anionic subsite at
the bottom of the gorge, (b) peripheral anionic site inhibitors
which bind at the entrance to the gorge, or (c) elongated
gorge-spanning inhibitors which bridge the two sites.6 The
extended bis(quaternary ammonium) dications, such as 1,10-
bis(trimethylammonium)decane (decamethonium), succi-
nylcholine (suxamethonium), and BW284c51 (1,5-bis(4-
allyldimethylammoniumphenyl)pentan-3-one), are potent
reversible “gorge-spanning” inhibitors that interact with
both the active and peripheral sites, which are located
The vast majority of host-guest complexes of CB[7] with
cationic guests, such as methylviologen,19 assemble such that
the cationic portion of the guest is located outside of the
cavity, adjacent to the oxygens of the portal carbonyls, with
the remaining hydrophobic portion of the guest positioned
inside the cavity. We have shown that for the
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12-15 A apart. Crystal structures of Torpedo californica
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acetylcholinesterase (TcAChE) with the BW284c517 and
decamethonium8 inhibitors indicate that they occupy similar
peripheral binding sites. Succinylcholine has been used as a
potent nicotinic acetylcholine receptor (nAcR) blocker and
depolarizing neuromuscular relaxant for over 50 years,
although it is not without multiple side effects.9
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