Inhibition of High‐Affinity Choline Uptake and Acetylcholine Synthesis by Quinuclidinyl and Hemicholinium Derivatives

Abstract

Choline uptake into cholinergic neurons for acetylcholine (ACh) synthesis is by a specific, high-affinity, sodium- and temperature-dependent transport mechanism (HAChU). To assess the role of choline availability in regulation of ACh synthesis, the structure-activity relationships of several hemicholinium (HC) and quinuclidinyl analogs were evaluated in a dose response manner. As confirms previous studies, the HCs, e.g., HC-3, acetylsecohemicholinium, and HC-15 are potent inhibitors of HAChU, HC-3 being the most potent (I50 = 6.1 X 10(-8) M). In the present study, the most potent quinuclidinyl derivative was the N-methyl-3-quinuclidinone (I50 = 5.6 X 10(-7) M). This compound had approximately 100-fold greater inhibitory activity than the corresponding racemic alcohol, suggesting that the 3-hydroxyl functional group is not absolutely essential for activity. Increasing the size of the N-functional group from a methyl to an allyl in the alcohol led to a 10-fold increase in activity. However, removal of the quaternizing N-methyl group yielding the tertiary amine, 3-quinuclidinol hydrochloride, greatly reduced its capacity to inhibit HAChU. Of the 2-benzylidene-3-quinuclidinone derivatives studied, only the m-chloro derivative significantly reduced HAChU.

Mass spectrometric study of selected precursors and degradation products of chemical warfare agents

“…19,20 Generally, quaternarization causes an increase in the inhibition of choline uptake in cholinergic neurons (regulation of acetylcholine synthesis) as has been studied with 3-quinuclidinol derivatives. 21 In the present work, a detailed fragmentation study of chemical warfare precursors is described. To our knowledge, this is the first study comprehensively covering the fragmentation pattern of these compounds using ion trap mass analyzer.…”

Inhibition of choline transport by redox-active cholinomimetic bis-catechol reagents

“…12 These results also suggested that 9, which also has two quaternary nitrogen atoms separated by twelve carbon atoms through two hydrophobic aromatic rings, has other constraints that dominate its improved binding to the transporter. 4 An increase in distance between the two quaternary nitrogen atoms also results in an increasing affinity for inhibition of CHT. 27…”

“…4 In order to probe selective cholinergic degradation, we have synthesized a unique series of cholinomimetic quaternary ammonium catechol-based molecules (Figure 1). 5-10 The defining structural features of this series include a quaternary ammonium group and a neighboring hydroxyl that produces a choline (Ch) analogue type affinity for cholinergic sites and a bulky, redox-active catechol moiety.…”

Molecular cloning and functional characterization of a neuronal choline transporter from

“…The HC3 inhibition constant for TrnCHT was estimated at 4.1 mM. Also, analogues of choline reported to be selective inhibitors of choline uptake in the mammalian cerebral cortex (IC 50 % 0:5 mM; Sterling et al, 1986) are weak inhibitors of [ 3 H]-choline uptake by TrnCHT. The experimental conditions used here to test the inhibitory ability of HC3 and quireston analogues involved exposing the TrnCHT expressing cells to [ 3 H]-choline and inhibitor simultaneously for 5 min.…”