Pharmacological Activity of the Carbon Analogue of Acetylcholine

Banister, Jean; Whittaker, V. P.

doi:10.1038/167605b0

Cited by 20 publications

(13 citation statements)

References 3 publications

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“…It had been claimed that molecules lacking charged head groups, such as dimethylbutylacetate, were capable of activating nicotinic channels (Banister & Whittaker, 1951;Saji & del Castillo, 1975). However, we found that delivery of this compound via a rapid microperfusion system to frog end-plates at concentrations up to 1 M did not elicit significant membrane currents.…”

Section: A Auerbach and Otherscontrasting

confidence: 39%

Correlation of agonist structure with acetylcholine receptor kinetics: studies on the frog end‐plate and on chick embryo muscle.

Auerbach¹,

Castillo²,

Specht³

et al. 1983

The Journal of Physiology

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SUMMARY1. The apparent lifetimes of frog end-plate channels activated by several nicotinic agonists have been determined with voltage-jump and fluctuation analysis techniques. The agonists were monoquaternary, N-substituted derivatives oftrimethylammonium (TMA).2. Methyl TMA activated channels which had apparent lifetimes about 3-4 times shorter than acetylcholine (ACh)-activated channels. This result was confirmed with single-channel recordings from embryonic chick skeletal muscle. Channel conductance and voltage dependence of channel lifetime were similar for methyl TMA-and ACh-activated channels. Methyl TMA showed no signs of blocking open end-plate channels.3. Ethyl TMA, acetylthiocholine, cholinethiol and carbamylcholine all activated channels similar to methyl TMA-activated channels with regard to lifetime. None of these agonists appeared to block end-plate channels in the employed concentrations.4. 4-ketopentyl TMA, which contains a methylene group in place of the ether oxygen of ACh, sometimes opened end-plate channels with similar apparent lifetimes as those opened by ACh. Single-channel recordings showed that bursts ofcurrent from channels activated by 4-ketopentyl TMA have similar durations as do those activated by ACh.5. Pentyl TMA and benzyl TMA block open end-plate channels even when delivered at doses which elicit very small currents.6. It is concluded that the ester moiety of ACh serves to stabilize the open conformation of the channel.

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Section: A Auerbach and Otherscontrasting

confidence: 39%

Correlation of agonist structure with acetylcholine receptor kinetics: studies on the frog end‐plate and on chick embryo muscle.

Auerbach¹,

Castillo²,

Specht³

et al. 1983

The Journal of Physiology

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“…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.…”

mentioning

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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“…Alternatively, they may form additional hydrogen bonds to other active site residues. (9) and (B) quercetin (12) in complex with the human M 1 mAChR model obtained from induced-fit docking using Glide v5.7 and Prime v3.0 (Schrödinger LLC), showing pi-pi stacking interactions (green lines), hydrogen bonds involving backbone atoms (solid purple arrows) and hydrogen bonds involving side-chain atoms (dashed purple arrows). Negatively-charged, polar and hydrophobic residues are depicted with red, light blue and green circles, respectively.…”

Section: Molecular Modellingmentioning

confidence: 99%

“…Flavonols 9-10 were synthesised from the corresponding 2'-hydroxyacetophenones and benzaldehydes to produce chalcones, followed by cyclisation under the Algar-Flynn-Oyamada [19,20] reaction conditions (Scheme 2). Apigenin (5), luteolin (6), diosmetin (7), fisetin (8), kaempferol (11), quercetin (12) and myricetin (13) were obtained from commercial sources. …”

Section: Synthesis Of Flavones and Flavonolsmentioning

confidence: 99%

“…Most mAChR active ligands contain a positively-charged ammonium group under physiological conditions, but the fact that there are examples of active compounds that lack this feature [12][13][14][15] suggests that this may not be an absolute requirement. In our laboratory, we have previously identified a group of six polyoxygenated flavones from the bark extract of Melicope subunifoliolata (Stapf) T.G.…”

Section: Introductionmentioning

confidence: 99%

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Flavonoids with M1 Muscarinic Acetylcholine Receptor Binding Activity

et al. 2014

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Muscarinic acetylcholine receptor-active compounds have potential for the treatment of Alzheimer's disease. In this study, a series of natural and synthetic flavones and flavonols was assayed in vitro for their ability to inhibit radioligand binding at human cloned M 1 muscarinic receptors. Several compounds were found to possess competitive binding affinity (K i = 40-110 µM), comparable to that of acetylcholine (K i = 59 µM). Despite the fact that these compounds lack a positively-charged ammonium group under physiological conditions, molecular modelling studies suggested that they bind to the orthosteric site of the receptor, mainly through non-polar interactions.

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Pharmacological Activity of the Carbon Analogue of Acetylcholine

Cited by 20 publications

References 3 publications

Correlation of agonist structure with acetylcholine receptor kinetics: studies on the frog end‐plate and on chick embryo muscle.

Correlation of agonist structure with acetylcholine receptor kinetics: studies on the frog end‐plate and on chick embryo muscle.

The Role of Ionic Interaction at the Muscarinic Receptor

Flavonoids with M1 Muscarinic Acetylcholine Receptor Binding Activity

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