Synthesis and biological activity of a 2-bromoethylamine (mustard) derivative of hemicholinium-3 and hemicholinium-15

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Abstract
Work on the synthesis and investigation into the biological activity of a 2-bromoethylamine (mustard) analogue of hemicholinium-3 (HC-3) and hemicholinium-15 (HC-15) is reported. Hemicholinium-3 bromo mustard (HC3-BrM, 5) and hemicholinium-15 bromo mustard (HC15-BrM, 11) cyclize in aqueous solution to a biethylenimine derivative (6) and a monoethylenimine derivative (12) that are structurally almost identical with HC-3 (1) and HC-15 (8), respectively. As with HC-3 or HC-15, these mustards strongly inhibited sodium-dependent, high-affinity choline uptake (SDHACU) activity in vitro. This inhibitory activity was found to result solely from the interaction of the cyclized ethylenimine form of the mustards with the uptake system. When compared on an equivalent concentration basis, HC3-BrM effected substantially greater inhibition of SDHACU than HC-3 and is, thus, at present the most potent known synthetic inhibitor of this uptake system. Synaptosomes incubated with a low concentration of precyclized HC3-BrM (25 nM) and then treated to remove all free and reversibly bound drug exhibited a maintained reduction (approximately 32%) in the Vmax of SDHACU activity. This behavior is in marked contrast to the findings with HC-3, the inhibition of which was totally removed by simple washing. It is suggested that the biethylenimine form of HC3-BrM undergoes a covalent, and thus possibly irreversible, bond formation with group(s) functionally involved with the SDHACU system.

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