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Molecular Pharmacology, Vol 11, 19-27, Copyright © 1975 by the American Society for Pharmacology and Experimental Therapeutics

Inhibition of High-Affinity Choline Transport in Rat Striatal Synaptosomes by Alkyl Bisquaternary Ammonium Compounds

J. T. HOLDEN 1, J. ROSSIER 1, J. C. BEAUJOUAN 1, P. GUYENET 1, and J. GLOWINSKI 1

1 Groupe NB (INSERM U.114), Laboratoire de Biologie Moléculaire, Collège de France, Paris 5e, France

The high-affinity choline transport system in rat striatal synaptosomes was inhibited competitively by a series of long-chain alkyl bisquaternary ammonium compounds. BTE18 [octadecamethylenebis(triethylammonium bromide)] had a Ki value of 28 nM, and BHDM18 [octadecamethylenebis((2-hydroxyethyl)dimethylammonium bromide)] had a Ki value of 75 nM. BTE18 and hemicholinium-3 (HC-3) were equipotent competitive inhibitors. The transport of neither tryptophan nor dopamine was inhibited significantly by these compounds. Inhibitory activity increased as the alkyl chain length was increased, but reached a maximum at 17 or 18 methylene groups for bistriethyl- and bistrimethylammonium compounds. Triethylammonium compounds were more active than trimethylammonium compounds. Monoquaternary alkyltrimethylammonium compounds with 5-12 methylene groups were at least as active as the corresponding bis compounds. Various other choline-related analogues yielded the following findings. Hemicholinium-15 was much less active than HC-3. Troxonium and troxypyrrolium tosylate were moderately effective inhibitors, as was the cholinesterase inhibitor BW 284 C51. Long-chain alkyl bisquaternary ammonium compounds may be useful high-affinity analogues in studying the properties of this synaptosomal choline transport system.

Note:
ACKNOWLEDGMENT The authors are indebted to Dr. Pierre Lefresne for his generous assistance and invaluable advice during this investigation.

Submitted on July 30, 1974




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