{'fraction_non_alphanumeric': 0.04672897196261682, 'fraction_numerical': 0.020129403306973402, 'mean_word_length': 6.065989847715736, 'pattern_counts': {'":': 0, '<': 0, '<?xml version=': 0, '>': 0, 'https://': 0, 'lorem ipsum': 0, 'www.': 0, 'xml': 0}, 'pii_count': 0, 'substrings_counts': 0, 'word_list_counts': {'cursed_substrings.json': 0, 'profanity_word_list.json': 0, 'sexual_word_list.json': 0, 'zh_pornsignals.json': 0}}
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 × 10−8M). In the present study, the most potent quinuclidinyl derivative was the N‐methyl‐3‐quinuclidinone (I50= 5.6 × 10−7M). 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.