Hydrophobic binding site in acetylcholinesterase

Steinberg, George M.; Mednick, Morton L.; Maddox, Jan P.; Rice, Robert L.; Cramer, Joyce A.

doi:10.1021/jm00245a002

Cited by 73 publications

(31 citation statements)

References 2 publications

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“…It is clear that THA is not an irreversible inhibitor of acetylcholinesterase, as the inhibition was not timedependent and was rapidly reversible by dilution. The results indicate that THA does not bind to the catalytic ('esteratic') site and it has been suggested by others (Steinberg et al, 1975) Freedman et al, 1988).…”

Section: Discussionsupporting

confidence: 76%

The cholinergic pharmacology of tetrahydroaminoacridine in vivo and in vitro

Hunter¹,

Murray²,

Jones³

et al. 1989

British J Pharmacology

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1 The effect of tetrahydroaminoacridine (THA) on cholinergically mediated behaviour in the rat and mouse has been investigated. In addition the actions of this compound on cholinesterase activity and on muscarinic and nicotinic receptors has also been examined. 2 Administration of THA (5-20mgkg-1, i.p.) produced a dose-dependent increase in tremor, hypothermia and salivation in both rats and mice. A similar profile of activity was seen following physostigmine (0.1-0.6 mg kg -1) administration. 3 THA was approximately fifty fold less potent than physostigmine in inducing behavioural change but its effects persisted for over twice as long as those of physostigmine. For example THA-induced hypothermia was still present at 4 h in the mouse and 8 h in the rat. 4 In vitro THA was a potent non-competitive inhibitor of rat brain cholinesterase (IC50: 57 + 6 nM) and bovine erythrocyte acetylcholinesterase (IC50: 50 + 10 nm) but was a more potent inhibitor of horse serum butyrylcholinesterase (IC50: 7.2 + 1.4 nM). 5 Radioligand binding studies indicated that THA binds non-selectively but with moderate potency to both M1 (Ki: 600nM) and M2 (Ki: 880nM) muscarinic receptors. THA also interacted with the allosteric site present on cardiac M2 receptors.

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Section: Discussionsupporting

confidence: 76%

The cholinergic pharmacology of tetrahydroaminoacridine in vivo and in vitro

Hunter¹,

Murray²,

Jones³

et al. 1989

British J Pharmacology

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“…This mechanism of action does not appear in Iine with reports indicating that THA interacts with AChE in a noncompetitive way (Hunter et al 1989;Wu and Yang 1989). However, this point is still controversial since according to Steinberg et al (1975), Nielsen et al (1989) and to our own experiments (unpublished observation), there is a substantial component of competitive action on THA's inhibitory effect. Finally, also the possibility that mechanism(s) other than AChE protection may be involved in THA antidotal action, deserves attention.…”

Section: Discussionmentioning

confidence: 87%

“…THA is a polycyclic primary amine endowed with potent inhibitory activity towards both AChE and butyrylcholinesterase (BuChE; EC 3.1.1.8) (Kaul 1962;Steinberg et al 1975;Hunter et al 1989). Interest in this drug arises mainly from reports indicating that is effective in improving the clinical condition of certain patients with Alzheimer's disease (Summers et al 1989).…”

Section: Introductionmentioning

confidence: 99%

Effectiveness of 1,2,3,4-Tetrahydro-9-aminoacridine (THA) as a pretreatment drug for protection of mice from acute diisopropylfluorophosphate (DFP) intoxication

Galli

Mori

1991

Arch Toxicol

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The protective action of 1,2,3,4-tetrahydro-9-aminoacridine (THA) against acute diisopropylfluorophosphate (DFP) intoxication was evaluated in mice by measuring the effects of the pretreatment of the animals with various doses of the drug on the DFP LD50. In the same experiments, the action of physostigmine and pyridostigmine were compared. THA at the doses 2.5, 5 and 7.5 mg/kg injected subcutaneously 15 min before DFP caused a dose-dependent increase in the DFP LD50, resulting in protection ratios equal to 3, 3.1 and 4.4, respectively, in the absence of atropine and 4.5, 8.6 and 14.5, respectively, in the absence of atropine and 4.5, 8.6 and 14.5, respectively, in the presence of atropine sulfate (17.4 mg/kg) therapy. Under the same experimental conditions, the protective ratios of 0.1 mg/kg physostigmine and pyridostigmine were 2.2 and 1.3, respectively, without atropine and 11.0 and 12.2, respectively, with atropine. The effectiveness of THA antidotal effect was inversely correlated to the time between pretreatment and DFP administration, being maximal when THA was injected 15 min before poisoning. In separate experiments, the time-course of acetylcholinesterase (AChE; EC 3.1.1.7) activity recovery was evaluated in the whole brain and diaphragm tissues of mice pretreated with THA (5 mg/kg) and physostigmine (0.1 mg/kg) 15 min before poisoning with DFP (8 mg/kg). At 10 min after DFP administration residual AChE activity in the brain averaged 4, 25 and 15% of that in controls in the animals pretreated with atropine alone, atropine plus THA or atropine plus physostigmine, respectively. At 24 h after poisoning, brain AChE activity averaged 34 and 47% of that in controls in the mice protected by THA and physostigmine, respectively. As for the diaphragm, AChE activity in THA-pretreated animals was 29% of controls 10 min after poisoning versus 8 and 23% in unprotected and physostigmine-pretreated animals, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

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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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Hydrophobic binding site in acetylcholinesterase

Cited by 73 publications

References 2 publications

The cholinergic pharmacology of tetrahydroaminoacridine in vivo and in vitro

The cholinergic pharmacology of tetrahydroaminoacridine in vivo and in vitro

Effectiveness of 1,2,3,4-Tetrahydro-9-aminoacridine (THA) as a pretreatment drug for protection of mice from acute diisopropylfluorophosphate (DFP) intoxication

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

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