The Pharmacology of Some New Anti‐cholinesterases

Shaw, F. H.; Bentley, G. A.

doi:10.1038/icb.1953.62

Cited by 77 publications

(24 citation statements)

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“…It has also been reported that nicotine will stimulate striatal 5-HT release (Westfall et al, 1983). In addition to its inhibitory activity against AChE (Shaw & Bentley, 1953;Steinberg et al, 1975) THA is centrally active at both muscarinic and, more weakly, at nicotinic receptors (Nilsson et al, 1987;Hunter et al, 1989;Perry et al, 1988;Pearce & Potter, 1988). It was feasible therefore that THA might modulate monoamine release via ACh receptors, either through a direct action or by increasing the concentration of ACh.…”

Section: Effect Of Tha On S-ht Reuptakementioning

confidence: 99%

The mechanism of tetrahydroaminoacridine‐evoked release of endogenous 5‐hydroxytryptamine and dopamine from rat brain tissue prisms

Robinson¹,

Souza²,

Cross³

et al. 1989

British J Pharmacology

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1 Tetrahydroaminoacridine (THA) is an acetylcholinesterase (AChE) inhibitor which may have a greater therapeutic effect in Alzheimer-type dementia (ATD) than other cholinergic agents. This suggests possible non-cholinergic properties. We have therefore studied the effects of THA on the release of endogenous 5-hydroxytryptamine (5-HT) from rat cortical prisms and dopamine from striatal prisms. 2 In the presence of K+ (1 mM), THA stimulated release of both 5-HT and dopamine. THA (100pM)-evoked monoamine release was comparable, but not additive with the release produced by K+ (35 mM). The effect was not maximal at 1 mm THA. THA-evoked release of 5-HT was independent of the presence of Ca2 + in the external medium.3 Drugs acting on the cholinergic system, nicotine, mecamylamine, atropine, oxotremorine, physostigmine and neostigmine (all 10pM) had no effect on 5-HT and dopamine release. 4-Aminopyridine (4-AP), a potent acetylcholine-releasing agent, had no effect on 5-HT release and was approximately 100 fold less active than THA on dopamine release. 4 Both THA and reserpine enhanced the release of 5-HT in the presence of the monoamine oxidase inhibitor, pargyline. Reserpine-but not THA-evoked release was abolished in the absence of pargyline. Reserpine (5mg kg -', i.p.) markedly depleted brain monoamine concentrations 3 h after injection, while THA (15 mg kg-1, i.p.) had no effect. 5 Chloroamphetamine and fenfluramine both released 5-HT in a Ca2+-independent manner and with a similar potency to THA, while (+)-amphetamine released dopamine with a similar potency to THA. The effects of the amphetamines were not maximal at 1 mm. However, unlike THA, chloroamphetamine-evoked release of 5-HT was additive with release evoked by K+ (35 mM).6 Clomipramine (IC5o = 0.036upM), imipramine (IC50 = 0.20 pM) and THA (IC50 = 19.9 pM) all inhibited the uptake of [3H]-5-HT into a P2 membrane preparation. However, none of these compounds inhibited [3H]-5-HT uptake into tissue prisms during the release experiments in which the reuptake inhibitor fluoxetine (5puM) was present. 7 We conclude that THA does not release endogenous 5-HT through a cholinergic, reserpine-or amphetamine-like mechanism or through inhibition of reuptake. The possibility exists that the release may occur via blockade of 4-AP-insensitive K+ channels.

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Section: Effect Of Tha On S-ht Reuptakementioning

confidence: 99%

The mechanism of tetrahydroaminoacridine‐evoked release of endogenous 5‐hydroxytryptamine and dopamine from rat brain tissue prisms

Robinson¹,

Souza²,

Cross³

et al. 1989

British J Pharmacology

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“…These mixed results were due to the short half-life of physostigmine (15 -30 min) (18,19) and, presumably, peripheral side effects. Tacrine is another ChE inhibitor (20,21) and Summers et al (22) showed improvement of memory score in six out of twelve AD patients who received oral tacrine. This study spurred the development of cholinergic drugs for AD.…”

Section: Cholinergic Hypothesismentioning

confidence: 99%

Research and Development of Donepezil Hydrochloride, a New Type of Acetylcholinesterase Inhibitor

Sugimoto

Ogura

Arai

et al. 2002

Japanese Journal of Pharmacology

201

129

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ABSTRACT-A wide range of evidence shows that cholinesterase (ChE) inhibitors can interfere with the progression of Alzheimer's disease (AD). The earliest known ChE inhibitors, namely, physostigmine and tacrine, showed modest improvement in the cognitive function of AD patients. However, clinical studies show that physostigmine has poor oral activity, brain penetration and pharmacokinetic parameters, while tacrine has hepatotoxic liability. Studies were then focused on finding a new type of acetylcholinesterase (AChE) inhibitor that would overcome the disadvantages of these two compounds. During the study, by chance we found a seed compound. We then conducted a structure-activity relationship study of this compound. After four years of exploratory research, we found donepezil hydrochloride (donepezil). Donepezil showed several positive characteristics including the following: 1) It has a novel structure compared to other conventional ChE inhibitors; 2) It shows strong anti-AChE activity and has long lasting efficacy; 3) The inhibitory characteristic of donepezil shows that it is highly selective for AChE as compared to butyrylcholinesterase (BuChE) and showed reversibility; 4) The results of clinical studies on donepezil show a very high significant difference on ADAS cog and CIBIC plus scores of AD patients. Donepezil is currently marketed in 56 countries all over the world.

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“…Compounds bearing thiazole moiety have been reported to exhibit a wide spectrum of biological effects including anticholinesterase activity [10][11][12][13][14][15][16] . …”

Section: Introductionmentioning

confidence: 99%

Synthesis and biological evaluation of some thiazole derivatives as new cholinesterase inhibitors

Turan-Zitouni

Özdemır

Kaplancıklı

et al. 2012

Journal of Enzyme Inhibition and Medicinal Chemistry

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The Pharmacology of Some New Anti‐cholinesterases

Cited by 77 publications

References 0 publications

The mechanism of tetrahydroaminoacridine‐evoked release of endogenous 5‐hydroxytryptamine and dopamine from rat brain tissue prisms

The mechanism of tetrahydroaminoacridine‐evoked release of endogenous 5‐hydroxytryptamine and dopamine from rat brain tissue prisms

Research and Development of Donepezil Hydrochloride, a New Type of Acetylcholinesterase Inhibitor

Synthesis and biological evaluation of some thiazole derivatives as new cholinesterase inhibitors

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