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TABLE 4-2. Anticholinesterase Effects of ChEIs in Vitro
IC
50
(mM)
ChEI
AChE (rat cortex)
BuChE (rat serum)
Ki* (nM)
HA
0.082
74.43
24.9
Galanthamine
1.995
12.59
210.0
Donepezil
0.010
5.01
12.5
Tacrine
0.093
0.074
105.0
*
Assayed with erythrocyte membrane AchE. Data from Ref. 35.
4.4
PHARMACOLOGY
4.4.1
Effects on Cholinesterase Activity
The cholinesterase (ChE) inhibition activity of HA has been evaluated in vitro and
in vivo by Tang et al. using spectrophotometric methods
34
with slight modifica-
tions.
3,35
The concentration of the inhibitor yielding 50% inhibition of enzyme
activity (IC
50
) of HA on AChE and butyrylcholinesterase (BuChE) compared
with other ChE inhibitors is listed in Table 4-2. HA initiated AChE (rat cortex) inhi-
bition at 10 nM. The anti-AChE activity of HA was more effective than that of
tacrine and galanthamine, but less than that of donepezil. The pattern of inhibition
is of the mixed competitive type. In contrast, HA inhibited BuChE at a much higher
concentration than donepezil, whereas tacrine was more potent toward BuChE. HA
has the highest specificity for AChE. The K
i
values (inhibition constants, in nM)
revealed that HA was more potent than tacrine and galanthamine, but about two-
fold less potent than donepezil (Table 4-2).
Compared with AChE in animals such as horse and rat, HA is a weaker inhibitor
of human serum BuChE. This selectivity for AChE as opposed to BuChE (similar to
that of galanthamine) may suggest a better side-effects profile.
36
However, a stron-
ger inhibition of BuChE could be important in the later stage of AD
37
and could
offer more protection over amyloid b-peptide (Ab) plaque deposition.
38
In contrast
to isoflurophate, the AChE activity did not decrease with the prolongation of incu-
bation with HA in vitro, and the AChE activity returned to 94% of the control after
being washed five times, which indicates a reversible inhibitory action.
3
Significant inhibition of AChE activity was demonstrated in the cortex, hippo-
campus, striatum, medial septum, medulla oblongata, cerebellum, and hypothala-
mus of rats that were sacrificed 30 min after the administration of HA at several
dose levels compared with saline control.
39-41
After administration of oral HA at doses of 0.12-0.5 mg/kg, a clear, dose-depen-
dent inhibition of AChE was demonstrated in the brains of rats.
39,40
In contrast to the
AChE inhibition in vitro, the relative inhibitory effect of oral HA over AChE was
found to be about 24- and 180-fold, on an equimolar basis, more potent than donepezil
and tacrine, respectively. In rats, HA injected intraperitoneally (i.p.) exhibited similar
efficacy of AChE inhibition as demonstrated after oral administration, whereas
i.p. administration of tacrine and donepezil showed greater inhibition on both
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