Hemicholinium-3 and related ether analogues on the synthesis of acetylcholine by mouse brain (in vitro)
Bove, F.C.; Haarstad, V.B.
Archives Internationales de Pharmacodynamie et de Therapie 253(2): 278-293
1981
ISSN/ISBN: 0003-9780 PMID: 7325764 Document Number: 171863
Incubation of minces prepared from whole brains of mice in high (25 mM) K+ (HK) medium resulted in the synthesis and release of > 4 times the acetylcholine (ACh) formed and released from non-depolarized minces incubated in low (4 mM) K+ (LK) medium; K+-depolarized minces accumulated only 2/3 of the ACh retained by non-depolarized minces. The Ca2+-dependent release of ACh evoked by K+-induced depolarization appears to consist primarily of newly formed transmitter, since this release was inhibited within 1 min after the addition of 0.1 .mu.M hemicholinium-3 (HC-3) and was promptly reversed by choline. The Ca2+-independent spontaneous release of ACh from non-depolarized minces was reduced only when the concentration of HC-3 was increased to 10 .mu.M. The ethyl acetal derivative of the hemiacetal tautomer of HC-3 and DMAE , the tetraethyl ether of the seco tautomer of HC-3, were equipotent to HC-3 as inhibitors of ACh synthesis by non-depolarized minces but only 1/3 as active as the parent compound on K-depolarized minces. The methyl and n-propyl acetal derivatives of hemiacetal HC-3 were significantly less active than HC-3 as inhibitors of ACh synthesis by both K-depolarized and non-depolarized minces. The hemicholinium acetals and DMAE were significantly more active than HC-3 as postjunctional inhibitors of ACh-induced contractions of the frog rectus abdominus muscle. Inhibitory activities of the hemicholiniums on choline acetyltransferase and cholinesterases were low and did not account for differences in prejunctional and postjunctional activities. The active moiety responsible for the primary action of HC-3 on ACh synthesis is discussed.