Effects of acetylcholine mustard aziridinium ion and its choline analogue on choline transport into synaptosomes

Rylett, B. Jane; Colhoun, E. H.

doi:10.1139/y77-104

Cited by 18 publications

(3 citation statements)

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“…Subsequently, Rylett & Colhoun (1977) investigated the effects of ChM on choline uptake and ACh synthesis in rat brain synaptosomes, and showed that it caused alkylation of the high affinity choline carrier which is involved in ACh synthesis. Further work by these authors has shown that ChM can also alkylate choline acetyltransferase, but that this occurs only in intact synaptosomes and not when the enzyme is studied in solution.…”

Section: Introductionmentioning

confidence: 99%

The effect of choline mustard on the rat superior cervical ganglia

Allen

1983

British J Pharmacology

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The effect of choline mustard aziridinium ion (ChM) on the isolated superior cervical ganglion of the rat was investigated. In the presence of ChM (22.5 microM), stimulation at 1 Hz resulted in a slowly developing blockade of transmission, which did not occur at a stimulus frequency of 0.1 Hz. Choline (0.1 mM) slowed the onset of the blockade produced by stimulation at 1 Hz in the presence of ChM. The presence of excess thiosulphate ions prevented the action of ChM on the transmission in the superior cervical ganglion. Treatment of the ganglion with ChM (22.5 microM) only slightly inhibited the depolarization produced by carbachol (dose ratio 1.3), suggesting the drug produced a small degree of receptor blockade. [3H]-choline accumulation in the rat superior cervical ganglia displays several components: (a) sodium-dependent high affinity uptake (SDHAU) that can be activated further by preincubation in a high concentration of K+ ions; (b) sodium-dependent low affinity uptake (SILAU); (c) linear diffusional accumulation which does not saturate. Hemicholinium-3 selectively inhibits the activated sodium-dependent high affinity uptake, but is a weak inhibitor of resting sodium-dependent high affinity uptake and sodium-independent low affinity uptake. ChM inhibits both activated and resting sodium-dependent high affinity uptake, but is a very weak inhibitor of sodium-independent low affinity uptake. Homocholine shows similar selectivity. ChM inhibition of activated sodium-dependent high affinity uptake is very much more persistent than that of hemicholinium-3. Hemicholinium-3 and ChM both inhibit [3H]-acetylcholine synthesis.

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Section: Introductionmentioning

confidence: 99%

The effect of choline mustard on the rat superior cervical ganglia

Allen

1983

British J Pharmacology

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“…Aziridinium derivatives of choline mustard analogs have been developed to act as irreversible inhibitors of high-affinity choline uptake (Rylett and Colhoun, 1977;Fisher and Hanin, 1980). Their potential as selective cholinergic cytotoxins was popularized by Fisher and Hanin (1980), and initial reports indicated that one of them, monoethylcholine mustard aziridinium ion, (ECMA, often referred to as AF64A), caused prolonged cholinergic hypofunction (Mantione et al,198 1).…”

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The toxic effects of ethylcholine mustard aziridinium ion on cholinergic cells in the chicken retina

Millar¹,

Ishimoto²,

Boelen³

et al. 1987

J. Neurosci.

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The chicken retina has been used to examine the toxicity of a highly reactive chemical analog of choline, ethylcholine mustard aziridinium ion (ECMA). Following a single intravitreal injection, retinas were analyzed biochemically for CAT and AChE activities, and GABA, glycine, and dopamine levels. Retinas were also examined using histofluorescence for dopamine histochemistry, for AChE, and immunohistochemistry with antibodies to CAT, tyrosine hydroxylase, GABA, 5-HT, Leu-enkephalin, and somatostatin. A dose of 50 nmol ECMA caused a prolonged 70% depletion of CAT activity and a 40% depletion of AChE activity. The other biochemical parameters were unchanged. This result corresponds to the morphological finding that 2 populations of cholinergic cells were destroyed and that the AChE activity associated with their terminal arbors was lost. A third population of cholinergic cells, located towards the middle of the inner nuclear layer, was resistant to the toxic effects of ECMA. The other cell types, except for somatostatin-immunoreactive cells and photoreceptors, which showed transient effects, were unaffected. ECMA therefore appears to be a highly specific toxin for cholinergic cells in the retina.

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“…The products of this scission may retain appreciable biological activity, but not at the same sites as the parent compounds. Acetylcholine mustard, for example, undergoes rapid hydrolysis at alkaline p H (Clement & Colhoun 1975a) and Colhoun and his collaborators have shown that the aziridinium ion analogue of choline so formed has long-lasting effects at cholinergic nerve terminals (Clement & Colhoun 1975a), which may result primarily from irreversible inhibition of choline transport (Clement & Colhoun 1975b;Rylett & Colhoun 1977, 1980. Reversible inhibition of choline acetyltransferase has also been observed (Rylett & Colhoun 1979).…”

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Pathways of decomposition of propylbenzilylcholine mustard in neutral and alkaline solution

1982

Journal of Pharmacy and Pharmacology

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High-voltage electrophoresis has been used to follow the decomposition of propylbenzilylcholine mustard (PrBCM) in aqueous solution. Dilute solutions of PrBCM in 10 mM phosphate buffer, pH 7.5, or Krebs-Henseleit solution allowed to stand for 1 h at room temperature (22-24 degrees C) contain mainly the aziridinium ion derivative. At pH 7.5 the concentration of this ion declines slowly, giving rise first to the N-hydroxyethyl derivative and then ultimately, following hydrolysis of the ester bond, to NN-bis(2-hydroxyethyl)propylamine and benzilic acid. In contrast, in 5 mM NaOH the ester bond undergoes rapid hydrolysis, so that the major species present after 15 min at room temperature is the N-hydroxyethylaziridinium ion. This ion then undergoes slow reaction with hydroxy ion to yield the same final decomposition product, NN-bis(2-hydroxyethyl)propylamine, as is observed at pH 7.5.

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Effects of acetylcholine mustard aziridinium ion and its choline analogue on choline transport into synaptosomes

Cited by 18 publications

References 0 publications

The effect of choline mustard on the rat superior cervical ganglia

The effect of choline mustard on the rat superior cervical ganglia

The toxic effects of ethylcholine mustard aziridinium ion on cholinergic cells in the chicken retina

Pathways of decomposition of propylbenzilylcholine mustard in neutral and alkaline solution

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