Inhibition of high affinity choline uptake: Structure activity studies

Sodium-dependent, high affinity choline uptake in brain synaptosomes was inhibited by various choline analogues. When substituents were placed on the quaternary nitrogen, the compounds became weaker inhibitors as the bulk of the substituents increased. None of the compounds with changes in the hydroxyl group part, except for a bis-quaternary compound, were potent inhibitors. Increasing the oxygen-nitrogen distance resulted in a weaker inhibition. Data from crystallographic studies [M. E. Senko and M. Templeton, Acta crystallogr. 13, 281 (1960); and F. G. Canepa, Nature, Lond.207, 1152 (1965)] and inspection of Dreiding molecular models suggest an optimal oxygen-nitrogen distance of about 3.3 Å. These results support earlier suggestions that a hydroxyl group and a quaternary nitrogen are necessary for interaction with the carrier.