A New Series of Cholinesterase Inhibitors*

Long, J. P.; Schueler, F. W.

doi:10.1002/jps.3030430204

Cited by 73 publications

(17 citation statements)

References 13 publications

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“…It has been found that choline chloride reversed some effects of hemicholinium (Long & Schueler, 1954). In the present experiments choline chloride was injected in doses up to 16 mg/kg, but did not restore the hypertensive effect of eserine once it was blocked by hemicholinium.…”

Section: Resultscontrasting

confidence: 66%

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Effect of Guanethidine, Hemicholinium and Mebutamate on the Hypertensive Response to Eserine and Catechol Amines

Varagić

Vojvodić

1962

British Journal of Pharmacology and Chemotherapy

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Guanethidine, hemicholinium and mebutamate were used to study the site and mechanism of the hypertensive response to eserine in the rat. Guanethidine was found to block very effectively the hypertensive effect of eserine and to produce at the same time a very strong potentiation of the response to catechol amines. Hemicholinium, after a certain latent period, also blocked the effect of eserine, at the same time leaving the response to adrenaline and noradrenaline intact. Mebutamate was also found to block the effect of eserine. The results of the present experiments suggest that eserine produces a central adrenergic activation in the rat.

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Section: Resultscontrasting

confidence: 66%

“…At the arrow hemicholinium was injected in a dose of 7.46 mg/kg. The animal was kept on artificial respiration because hemicholinium depresses respiratory movements (Long & Schueler, 1954;Longo, 1959;Holmes & Wilson, 1960). Seven minutes after injection of hemicholinium the effect of eserine was depressed, as shown in A.…”

Section: Resultsmentioning

confidence: 99%

Effect of Guanethidine, Hemicholinium and Mebutamate on the Hypertensive Response to Eserine and Catechol Amines

Varagić

Vojvodić

1962

British Journal of Pharmacology and Chemotherapy

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“…The hemicholinium HC-3 was prepared as described by Long & Schueler (1954) Figure 1 show the changes in plasma choline concentrations which followed the injection of higher doses of the hemicholiniums sufficient to produce complete or almost complete respiratory failure. In these experiments two intravenous injections of either HC-3 (1.4,mol/kg) or TPHC-3 (0.7 ,umol/kg) were given 1 h apart.…”

Section: Methodsmentioning

confidence: 99%

Effect of Two Hemicholiniums on the Disposition and Distribution of Endogenous Free Choline in Anaesthetized Rabbits

Gardiner

Gwee

1977

British J Pharmacology

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1 The effects of hemicholinium no. 3 (HC‐3) and its p‐terphenyl analogue (TPHC‐3) on the disposition and distribution of free choline were studied in rabbits under pentobarbitone anaesthesia. Free choline was determined by bioassay. 2 The respiration of animals given 0.35 μmol/kg of HC‐3 was hardly affected; however, 4 out of 6 rabbits given the same dose of TPHC‐3 exhibited varying degrees of respiratory impairment. All animals that received 2 injections (1 h apart) of either HC‐3 (1.4 μmol/kg) or TPHC‐3 (0.7 μmol/kg) developed respiratory difficulty about 1 h after the second injection. 3 The respiratory distress was accompanied by a 2 to 15‐fold rise in plasma choline concentration. This rise has been attributed to hypoxia. 4 In experiments in which choline has been infused it was observed that HC‐3 could impair the animal's ability to dispose of exogenous choline. In control rabbits neither HC‐3 nor TPHC‐3 produced changes in plasma choline concentrations unless the respiration was depressed. 5 Either HC‐3 or TPHC‐3 (both at 0.35 μmol/kg) significantly (P < 0.05) reduced the kidney choline concentration by 40% and 30% respectively; both hemicholiniums raised the lung choline concentration by about 35%. Only TPHC‐3 caused a significant rise (40%) in liver choline. The choline concentrations in other tissues were unaffected by the hemicholiniums.

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“…The compound, u,cw-dibromo-4,4'-biacetophenone, which is a precursor for acetylseco HC-3, was prepared according to the method of HAARSTAI) and SCHUE~ER (unpublished observations) which is a modification of the method of LONG and SCHUELER (1954). Acetylseco HC-3 dibromide, [4,4'-diphenylylenebis (2-oxoethylene)] bis [(Zacetoxyethyl) dimethylammonium bromide], was prepared as follows: 0.5 g of ff,u-dibrom~,~-bia~tophenone was dissolved in SO ml of boiling tetrahydrofuran.…”

Section: Methodsmentioning

confidence: 99%

Acetylseco hemicholinium-3, a new choline acetyltransferase inhibitor useful in neuropharmacological studies

et al. 1973

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Summary-Describedare the synthesis and some aspects of the pharmacology of acetylseco hemicholinium-3 (acetylseco HC-3), the acetylated open ring analogue of hemicholinium-3 (HC-3). The effects of both compounds were determined in uiuo on rat brain acetylcholine (ACh), 'Y-choline (14C-Ch) incorporation into 14C-acetylcholine (14C-ACh) and on one way jump box avoidance and escape behavior in naive and trained rats. In addition, the in vitro effects of both drugs were determined on choline acetyltransferase activity (ChAc) in rat brain.When given intraventricularly in doses of l-20 pg both compounds reduced total ACh content in the brain to a maximum of 5'0% of normal in 30-60 min. In doses of 20 pg intraventricularly, both drugs also reduced 14C-Ch incorporation into Y-ACh by 845% for acetylseco HC-3 and by 52% for HC-3.The in viva changes of ACh in the brain were correlated with the behavioral deficits induced in one way shuttle box acquisition and retention. In doses of 20 pg total intraventri~ularly, both compounds produced behavioral deficits which were greater in naive than in trained animals. Zn vitro, acetylseco HC-3 inhibited ChAc activity with an 150 of 1 x 10e5 M with Ch IO-* M and acetyl CoA 6.4 x 10m4 M, while HC-3 had no inhibitory effects. Using rat brain homogenate as the enzyme source and commercial acetyl CoA for kinetic studies, acetylseco HC-3 was shown to be a mixed inhibitor of acetyl CoA and a competitive inhibitor of Ch.The in uiuo actions of acetyiseco HC-3 are consistent with those of a ChAc inhibitor. However, it is necessary to rule out the possibility that the drug may also compete with Ch for its transport across biological membranes like its deacetylated derivative HC-3.The hemicholiniums have been widely investigated since they were first synthesized in 1954 by LONG and SCHUELER. Hemicholinium-3 (HC-3) is the prototype compound of this series. This agent reduces tissue acetyfcholine (ACh), possibly by reducing the active transport of choline (Ch) as shown by MACINTOSH (1963) and HODGKIN and MARTIN (1965). However, other mechanisms such as a shift in Ch metabolism toward phospholipid formation (G~MEz, DOMINO and SELLINGER, 1970a,b;GOMEZ, SELLINGER, SANTIAGO and DOMINO, 1971) and production of a false neurotransmitter through acetyhttion (RODRIGUEZ DE LORES ARNAIZ, LIEBER and DE ROBERTIS, 1970) have been proposed. SCHUELER (1955) found that WC-3 was the most toxic of some 20 bis-quaternary derivatives studied. HC-10 or acetylseco hemicholinium-3 (acetylseco HC-3) produced a toxicological picture similar to HC-3. SCHUELER assumed that acetylseco HC-3 was hydrolyzed in viuo to HC-3. There was little evidence then that acetylseco HC-3 was pharmacologically different from HC-3.

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A New Series of Cholinesterase Inhibitors*

Cited by 73 publications

References 13 publications

Effect of Guanethidine, Hemicholinium and Mebutamate on the Hypertensive Response to Eserine and Catechol Amines

Effect of Guanethidine, Hemicholinium and Mebutamate on the Hypertensive Response to Eserine and Catechol Amines

Effect of Two Hemicholiniums on the Disposition and Distribution of Endogenous Free Choline in Anaesthetized Rabbits

Acetylseco hemicholinium-3, a new choline acetyltransferase inhibitor useful in neuropharmacological studies

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