The active structure of hemicholinium inhibiting the biosynthesis of acetylcholine

DiAugustine, Richard P.; Haarstad, Vernon B.

doi:10.1016/0006-2952(70)90212-1

Cited by 10 publications

(4 citation statements)

References 27 publications

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“…Each value is the average of 4 determinations ± s.e.mean of 10% or less. DiAugustine & Haarstad, 1970;Hemsworth, 197 lb;Barker & Mittag, 1975;Simon et al, 1975). Therefore, a further study of the hydroxypiperidinium compounds was made, using biochemical techniques, to try to determine how they might inhibit ACh synthesis.…”

Section: In Vitro Inhibition Of Chacmentioning

confidence: 99%

“…Hemicholinium-3 has a cyclic choline moiety which is structurally similar to 3-hydroxypiperidinium except that it is fixed in a morpholinium ring. Hemicholinium-3 is also acetylated by soluble ChAc (Hemsworth, 1971b), but it is not known for certain whether it is acetylated to a cyclic form of acetylhemicholinium-3 or whether it undergoes ring opening on the enzyme surface, to give open-chain acetyl-seco-hemicholinium-3 (DiAugustine & Haarstad, 1970;Barker & Mittag, 1975). Due to the stability of the piperidinium ring, it seems unlikely that 3-hydroxypiperidinium will undergo ring opening upon enzymatic acetylation.…”

Section: Anticholinesterase Activitymentioning

confidence: 99%

“…This reversal indicates that the analogues caused a prejunctional block by inhibiting the synthesis of ACh. Indeed, many choline analogues which have exhibited a prejunctional block on the rat diaphragm have also been shown to interfere with neuronal ACh synthesis (Bowman & Rand, 1962;Bowman & Hemsworth, 1965; DiAugustine & Haarstad, 1970;Hemsworth, 197 lb;Barker & Mittag, 1975;Simon et al, 1975). Therefore, a further study of the hydroxypiperidinium compounds was made, using biochemical techniques, to try to determine how they might inhibit ACh synthesis.…”

Section: Anticholinesterase Activitymentioning

confidence: 99%

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Pharmacological actions of some cyclic analogues of choline

Hemsworth

Shreeve

Veitch

1984

British J Pharmacology

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Two cyclic choline analogues (3‐hydroxy‐N,N‐dimethylpiperidinium and 2‐hydroxymethyl‐N,N‐dimethylpiperidinium) and two cyclic homocholine analogues (4‐hydroxy‐N,N‐dimethylpiperidinium and 3‐hydroxymethyl‐N,N‐dimethylpiperidinium) have been studied with regard to their actions at the cholinergic synapse. All the analogues had some direct depolarizing activity on the frog rectus abdominis muscle but they were less potent in this respect than acetylcholine. Compared to physostigmine, the analogues were weak inhibitors of Cholinesterase enzymes. All the analogues were found to have a presynaptic blocking action on the rat phrenic nerve‐hemidiaphragm preparation, which was reversed by choline. In addition, they all inhibited the high affinity transport of choline into synaptosomes but only the cyclic choline analogues were found to be acetylated by soluble choline acetyltransferase in vitro. We conclude that the hydroxypiperidinium analogues caused the presynaptic block seen at the neuromuscular junction by inhibiting acetylcholine synthesis.

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Section: In Vitro Inhibition Of Chacmentioning

confidence: 99%

Section: Anticholinesterase Activitymentioning

confidence: 99%

Section: Anticholinesterase Activitymentioning

confidence: 99%

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Pharmacological actions of some cyclic analogues of choline

Hemsworth

Shreeve

Veitch

1984

British J Pharmacology

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“…HC-3 also produced a transient depression of spike height accompanied by a slight hyperpolarization (DeAugustine and Haarstad, 1970).…”

Section: Effects On Autonomic Gangliamentioning

confidence: 99%

Acetylsecohemicholinium: Chemical and Pharmacological Evaluation of an Open-Ring Hemicholinium

Maggio-Cavaliere¹

1976

Pharmacology

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Acetylsecohemicholinium No. 3 (AcHC-3), the acetate of the open ring (seco form of hemicholinium No. 3, HC-3) hydrolyzes in vitro to the hemiacetal HC-3 at. pH values above 9, a temperature-dependent conversion illustrated by ultraviolet spectral shifts from 305 to 257 mμ, and to a limited extent by certain esterases as measured by manometric analysis. An LD₅₀ of 125μg/kg for a neutral solution of AcHC-3 was decreased to 78.3 μg/kg (the LD₅₀ of HC-3) upon being made basic. Prolonged treatment of mice with LD_10–20 doses of AcHC-3 was associated with decreased fatty acid oxidation in the liver and resulted in infiltration of fat into hepatic cells, a reaction preventable by treatment with small doses of choline (10 mg/kg). AcHC-3 causes neuromuscular and autonomic ganglionic blockade, cholinesterase inhibition, and in vitro inhibition of acetylcholine (ACh) synthesis. These actions, although HC-3-like, appear to be due to AcHC-3 rather than HC-3 since neither cholinesterase inhibition nor hepatic ligation altered the neuromuscular blocking actions of AcHC-3. In addition to its HC-3-like properties, AcHC-3 consistently produced a transient increase in twitch height of gastrocnemius muscle before blockade and was dose-responsive in depressing blood pressure and in eliciting contractions of the isolated guinea pig ileum. AcHC-3 is both a cholinomimetic (depresses arterial blood pressure, decreases heart rate and increases ileal contractions) and a competitor of acetylcholine. That is, in most preparations tested, AcHC-3 at lower concentrations has as much intrinsic activity as ACh and at somewhat higher concentrations competitively blocks the responses to ACh. These cholinomimetic

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Structure‐activity aspects of hemicholinium‐3 (HC‐3) and its analogs and congeners

Cannon¹

1994

Medicinal Research Reviews

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The active structure of hemicholinium inhibiting the biosynthesis of acetylcholine

Cited by 10 publications

References 27 publications

Pharmacological actions of some cyclic analogues of choline

Pharmacological actions of some cyclic analogues of choline

Acetylsecohemicholinium: Chemical and Pharmacological Evaluation of an Open-Ring Hemicholinium

Structure‐activity aspects of hemicholinium‐3 (HC‐3) and its analogs and congeners

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