The Active Site of Acetylcholinesterase and Related Esterases and its Reactivity towards Substrates and Inhibitors

Cohen, Jules; Oosterbaan, R.A.

doi:10.1007/978-3-642-99875-1_7

Cited by 47 publications

(21 citation statements)

References 189 publications

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“…The effect of charge on association between acetylcholine and acetylcholinesterase has been estimated by Wilson (1952) and by Cohen & Oosterbaan (1963). The mean effect of the charge was to increase affinity by a factor of 17, corresponding to a coulombic free energy of -1.75 kcals/mole.…”

Section: Discussionmentioning

confidence: 99%

The Role of Ionic Interaction at the Muscarinic Receptor

Burgen

1965

British Journal of Pharmacology and Chemotherapy

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It is commonly assumed by pharmacologists that the positively charged cationic group in such agonists as acetylcholine, noradrenaline and histamine is essential for their agonist action. The evidence in favour of this view is far from conclusive. Barlow & Hamilton (1962) examined the effect ofpH on the activity of nicotine in producing synaptic block of the rat phrenic nerve-diaphragm preparation. When compared with the quaternary nicotine N-methiodide the activity of nicotine was related to thepH in the way to be expected if the nicotinium ion were more active than the non-protonated form, but neither the range ofpH values studied nor the precision of the results were sufficient to establish the activity (if any) of the non-protonated nicotine relative to the nicotinium ion. Hamilton (1963) has shown a similar effect of pH in the action of nicotine on the frog rectus abdominus muscle, but in this case also the activity of the non-protonated form was not established. Ariens, Simonis & van Rossum (1964) were unable to discover any clear relationship between pH and the action of arecoline on the frog rectus, but did not extend their study over a wide enough pH range to obtain decisive results. Rocha e Silva (1961) examined the effect ofpH on the action of histamine. There was a clear pH-dependence below pH 7 but the action was independent of pH above 7. These results are compatible with the response to histamine being dependent on a group with a pKa 7.0. However, since the dissociation constants of the ionizable groups in histamine are pKaj, 5.9; pKa2, 9.7, the pH-dependence cannot be attributed to the change in histamine ionization and is probably due to a change in the charge on the receptors.An alternative approach to the problem is to study the activity of analogues of the agonist in which the basic nitrogen atom has been replaced by an atom with a different electron shell so that a cation is not formed. Banister & Whittaker (1951) examined the action of 3,3-dimethylbutyl acetate, the analogue of acetylcholine in which the basic nitrogen atom has been replaced by a carbon atom. On the frog rectus, this drug had about 1/12,000th the activity of acetylcholine and, on the guinea-pig ileum, the activity was small and maximal responses were not obtained. The analogue of histamine in which the primary amino-group is replaced by a hydroxyl group, H-(2-hydroxyethyl)-imidazole, is reported to have little or no histamine-like activity (Vartiainen, 1935;Schneedorf & Ivy, 1935;Grossman, Robertson & Rosiere, 1952). These latter pieces of evidence do suggest that uncharged analogues may have some activity and it seemed that the problem merited further examination in view of its importance for the theoretical interpretation of drugreceptor interactions.

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Section: Discussionmentioning

confidence: 99%

The Role of Ionic Interaction at the Muscarinic Receptor

Burgen

1965

British Journal of Pharmacology and Chemotherapy

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“…A calculation based on a k2 value of 1.1 (plmol min)1 for paraoxon with erythrocyte cholinesterase (Cohen & Oosterbaan, 1963) (Hobbiger et al, 1969).…”

Section: Methodsmentioning

confidence: 99%

The effect of gallamine, gallopamil and nifedipine on responses to acetylcholine and carbachol in the taenia of the guinea‐pig caecum

Mitchelson

Ziegler

1984

British J Pharmacology

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“…The inhibition ofAChE and related esterases, often referred to as serine hydrolases, has been clearly demonstrated to be the result of an actual chemical reaction between the enzyme and the organophosphate or carbamate ester (1)(2)(3). The phosphorylated or carbamylated enzyme is no longer capable of effecting the hydrolysis of ACh; this results in a buildup of the neurotransmitter at a nerve synapse or neuromuscular junction.…”

Section: Introductionmentioning

confidence: 99%

Mechanism of Action of Organophosphorus and Carbamate Insecticides

Fukuto¹

1990

Environmental Health Perspectives

206

255

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Organophosphorus and carbamate insecticides are toxic to insects and mammals by virtue of their ability to inactivate the enzyme acetylcholinesterase. This review addresses the mechanism of inhibition of acetylcholinesterase by organophosphorus and carbamate esters, focusing on structural requirements necessary for anticholinesterase activity. The inhibition of acetylcholinesterase by these compounds is discussed in terms of reactivity and steric effects. The role of metabolic activation or degradation in the overall intoxication process is also discussed.

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The Active Site of Acetylcholinesterase and Related Esterases and its Reactivity towards Substrates and Inhibitors

Cited by 47 publications

References 189 publications

The Role of Ionic Interaction at the Muscarinic Receptor

The Role of Ionic Interaction at the Muscarinic Receptor

The effect of gallamine, gallopamil and nifedipine on responses to acetylcholine and carbachol in the taenia of the guinea‐pig caecum

Mechanism of Action of Organophosphorus and Carbamate Insecticides

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