Pharmacological evaluation of novel Alzheimer's disease therapeutics:Acetylcholinesterase inhibitors related to galanthamine
G.M. Bores
Bok Engelsk 1996
| Utgitt | 1996
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| Omfang | Side 728- 738
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| Opplysninger | Acetylcholinesterase (AChE) inhibitors from several chemical classeshave been tested for the symptomatic treatment of Alzheimer'sdisease; however, the therapeutic success of these compounds has beenlimited. Recently, another AChE inhibitor, galanthamine hydrobromide(GAL), has shown increased clinical efficacy and safety. Usingbiochemical, behavioral and pharmacokinetic analyses, this reportcompares GAL with two of its analogs, 6-O-acetyl-6-O-demethylgalanthamine hydrochloride (P11012) and 6-O-demethyl-6-O-[(adamantan-1-yl)-carbonyl]galanthamine hydrochloride (P11149), fortheir therapeutic potential. P11012 and P11149 were found to bepotent, competitive and selective inhibitors of AChE, demonstratingcentral cholinergic activity, behavioral efficacy and safety. P11012and P11149, through pharmacokinetic analyses, were shown to act aspro-drugs, yielding significant levels of 6-O-demethylgalanthamine.In vitro, 6-O-demethylgalanthamine was 10- to 20-fold more potentthan GAL as an inhibitor of AChE, and it demonstrated greaterselectivity for inhibition of AChE vs. Butyrylcholinesterase. LikeGAL, both P11012 and P11149 showed central cholinergic activitybiochemically, by significantly inhibiting rat brain AChE;physiologically, by causing hypothermia; and behaviorally, byattenuating scopolamine-induced deficits in passive avoidance. Inaddition, GAL, P11012 and P11149 enhanced step-down passiveavoidance, another measure of behavioral efficacy. By comparingefficacious doses with primary overt effects, P11012 and P11149 hadbetter oral therapeutic indices than GAL. Oral pharmacokineticanalyses of GAL, P11012 and P11149 revealed differences. AlthoughP11012 and P11149 exhibited similar area under the curve values,P11149 had slower, lower and more sustained concentration maximumlevels. P11012 and GAL rapidly reached their concentration maximums,but GAL, in brain, had the highest area under the curve andconcentration maximum. Because of its composite profile, includingduration of action, oral therapeutic index and pharmacokinetics,P11149 is considered the better therapeutic candidate for thetreatment of Alzheimer's disease.
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| Emner |
