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

Abstract

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.

Muscarinic and Nicotinic Acetylcholine Receptor Agonists and Allosteric Modulators for the Treatment of Schizophrenia

“…These alterations are constistent with abnormalities in phospholipid membrane synthesis and integrity, but may also reflect impaired ChAT function. By contrast, other studies have found no changes or regional elevations in ChAT activity, indicating the potential for variability and/or artifacts with the use of postmortem brain tissues (eg, differences in tissue quality, postmortem interval, patient medication history, appropriate age-matched controls, and/ or small cohort sizes) (Domino et al, 1973;McGeer and McGeer, 1977). Limitations with these early pharmacological and postmortem studies further support the need to develop subtype-selective mAChR and nAChR ligands.…”

Mixed depressant and stimulant actions of morphine and their relationship to brain acetylcholine

“…We have used RC-3 and acetylseco HC-3 to inhibit the synthesis of ACh. Acetylseco RC-3 is used preferentially because of its dual mechanisms of action (inhibition of choline uptake and choline acetyltransferase), it provides less variability, and it is less toxic (42) .…”

Inhibition of human fetal brain acetylcholinesterase: Marker effect of neurotoxicity

“…Acetylcholinesterase has been tested in vitro as a predictor of the toxic potential of pesticides like organophosphate and carbamate compounds in white rats (El-Sebae et al, 1977;Chin et al, 1980) and goats (Guhathakurta and Bhattacharya, 1989). Besides pesticides, various psychotropic agents are known to influence the brain acetylcholineacetylcholinesterase concentration in rats (Naik and Sheth, 1970;Domino et al, 1973) and mice (Chabrier and Jacob, 1980). Some steroid contraceptives are found to decrease midbrain AChE activity (Bandyopadhyay and Ghosh, 1988).…”