Some Aspects of the Pharmacology of an Homologous Series of Choline Esters of Fatty Acids

Schneider, Robert; Timms, A. R.; Kyi, Zu-Yoong; Wilson, Warren J.

doi:10.1111/j.1476-5381.1957.tb01358.x

Cited by 18 publications

(13 citation statements)

References 16 publications

(13 reference statements)

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“…Similar findings have been reported for several series of related com-, pounds, for example, acetylcholine or Dilvaskne (Schneider & Timms 1957;van Rossum & Ariens, 1959;Koopman, 1960).…”

Section: Atropine-like Agents (The Potency As Po-or Pa~-values Is Gisupporting

confidence: 79%

Absolute configuration and parasympathetic action: Pharmacodynamics of enantiomorphic and diastereoisomeric esters of β-methylcholine

Ellenbroek

Nivard

Rossum

et al. 1965

Journal of Pharmacy and Pharmacology

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The parasympathomimetic and atropine-like actions of enantiomorphic esters of 8-methylcholine and various estcrs of choline or 8-methylcholine containing an asymmetric centre in the acid moiety have been studied. The potent parasympathomimetic drugs have a configuration identical with that of muscarine, suggesting a close affinity with the receptor. There is a gradual change from agonist to antagonist with increasing molecular size of the acid moiety, antagonism beginning with the butyric ester. Optimal affinity as a mimetic in the lower homologues is obtained with the acetic ester. Maximum affinity as an antagonist is obtained with the ester of the bulky hexahydrobenzilic acid. The configuration of the choline part is irrelevant for high atropine-like potency in the compounds derived from 8-methylcholine. Clear differences in affinity are found, however, between stereoisomers of potent antagonists containing an asymmetric centre in the acid moiety, provided the asymmetric carbon atom does not bear isosteric groups. It is concluded that the atropinelike agents, although being competitive antagonists of the parasympathomimetics at best cover the agonistic receptor area only partially.

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“…Similar findings have been reported for several series of related com-, pounds, for example, acetylcholine or Dilvaskne (Schneider & Timms 1957;van Rossum & Ariens, 1959;Koopman, 1960).…”

Section: Atropine-like Agents (The Potency As Po-or Pa~-values Is Gisupporting

confidence: 79%

Absolute configuration and parasympathetic action: Pharmacodynamics of enantiomorphic and diastereoisomeric esters of β-methylcholine

Ellenbroek

Nivard

Rossum

et al. 1965

Journal of Pharmacy and Pharmacology

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“…Those findings were further corroborated by several groups between 1914 and 1956. At that time, the pharmacological effects of acyl cholines was demonstrated on the isolated rabbit heart, isolated guinea-pig ileum, and the rat stomach [35]. The compounds measured in our datasets, considered long-chained acyl cholines, were found to block the effect of acetylcholine on the rabbit and guinea-pig tissues tested, and depressed spontaneous hydrochloric acid secretion by the rat stomach.…”

Section: Acyl Cholines Are Decreasedmentioning

confidence: 78%

Comprehensive Circulatory Metabolomics in ME/CFS Reveals Disrupted Metabolism of Acyl Lipids and Steroids

et al. 2020

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The latest worldwide prevalence rate projects that over 65 million patients suffer from myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), an illness with known effects on the functioning of the immune and nervous systems. We performed an extensive metabolomics analysis on the plasma of 52 female subjects, equally sampled between controls and ME/CFS patients, which delivered data for about 1750 blood compounds spanning 20 super-pathways, subdivided into 113 sub-pathways. Statistical analysis combined with pathway enrichment analysis points to a few disrupted metabolic pathways containing many unexplored compounds. The most intriguing finding concerns acyl cholines, belonging to the fatty acid metabolism sub-pathway of lipids, for which all compounds are consistently reduced in two distinct ME/CFS patient cohorts. We compiled the extremely limited knowledge about these compounds and regard them as promising in the quest to explain many of the ME/CFS symptoms. Another class of lipids with far-reaching activity on virtually all organ systems are steroids; androgenic, progestin, and corticosteroids are broadly reduced in our patient cohort. We also report on lower dipeptides and elevated sphingolipids abundance in patients compared to controls. Disturbances in the metabolism of many of these molecules can be linked to the profound organ system symptoms endured by ME/CFS patients.

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“…On the other hand, it is known that in the acyl cholines there is a rapid attenuation of muscarinic potency as the carbon chain on the carboxyl group is lengthened, so that butyrylcholine has less than 1% of the activity of acetylcholine on the guinea-pig intestine (Wurzel, 1959), but, with further lengthening of the acyl group, agonist activity becomes replaced by increasingly potent antagonist action (Schneider & Timms, 1957). A further substantial increase in antagonist potency results when a phenyl group is introduced into the acyl methyl group, as in diphenylacetylcholine and benziloylcholine (Barlow et al, 1963).…”

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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Some Aspects of the Pharmacology of an Homologous Series of Choline Esters of Fatty Acids

Cited by 18 publications

References 16 publications

Absolute configuration and parasympathetic action: Pharmacodynamics of enantiomorphic and diastereoisomeric esters of β-methylcholine

Absolute configuration and parasympathetic action: Pharmacodynamics of enantiomorphic and diastereoisomeric esters of β-methylcholine

Comprehensive Circulatory Metabolomics in ME/CFS Reveals Disrupted Metabolism of Acyl Lipids and Steroids

The Role of Ionic Interaction at the Muscarinic Receptor

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