title: 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.
mesh_terms: D000109:Acetylcholine / Q000096:biosynthesis*; D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D002540:Cerebral Cortex / Q000378:metabolism; D002794:Choline / Q000378:metabolism*; D006426:Hemicholinium 3 / Q000031:analogs & derivatives / Q000494:pharmacology*; D007700:Kinetics; D008297:Male; D011812:Quinuclidines / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D012964:Sodium / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013574:Synaptosomes / Q000187:drug effects / Q000378:metabolism*; D013696:Temperature
chemical_list: D011812:Quinuclidines; D006426:Hemicholinium 3; D012964:Sodium; D002794:Choline; D000109:Acetylcholine