CHARACTERIZATION OF THE EFFECT OF 2 4-METHYL PIPERIDINE-DERIVATIVES OF HEMICHOLINIUM-3, A-4 AND A-5, ON CHOLINE TRANSPORT

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  • 1 October 1990
    • journal article
    • research article
    • Vol. 255  (1) , 357-363
Abstract
A-4 and A-5 are tertiary and N-methy quaternary 4-methylpiperidine analogs of hemicholinium-3 (HC-3). Previous work in this laboratory has shown A-4 and A-5 to be inhibitors of the sodium-dependent, high affinity choline uptake system (SDHACU). Their effects on the choline transport were characterized further using neuroblastoma 41A3 cells. These cells rapidly take up choline through two separate mechanisms: a SDHACU system and a sodium-independent, low affinity uptake system (SILACU). A-4, A-5 and HC-3 decreased 5 .mu.M choline transport in a dose-dependent fashion. The compounds were unable to decrease choline transport at 250 .mu.M choline suggesting that they are inacitve with respect to SILACU. All three compounds significantly increased the Km but not the Vmax for the SDHACU system, suggesting a competitive mechanism of inhibition. K1 values ranged from 18 to 25 .mu.M for A-4, 20 to 26 .mu.M for A-5 and 68 to 75 .mu.M for HC-3. Dose-response curves for inhibition of choline transport by A-5 and HC-3 were not changed by a 24-hr preexposure of the cells to each inhibitor. However, after a 24-hr pre-exposure to A-4, a significantly different dose-response curve was obtained compared to the dose-response curve for A-4 in untreated cells. After a 24-hr pre-exposure, a 4-hr recovery period was sufficient to remove the effect of each compound. These data suggest that A-4 and A-5, like HC-3, inhibit the SDHACU, competitively and reversibly.