The effects of a hemicholinium analogue, HC-15, on neuromuscular transmission

Abstract

The bisected hemicholinium molecule HC-15, which is exactly half the HC-3 molecule, was investigated for neuromuscular blocking activity and its action compared to the effect of the parent compound. HC-15 was shown to inhibit neuromuscular transmission by both a pre- and a post-junctional action. Large doses of the compound produced a post-junctional, nondepolarizing block whereas after smaller doses a slowly developing block occured selectively in rapidly stimulated muscles which was not antagonized by anticholinesterase drugs. HC-15 inhibited both acetylcholinesterase and cholinesterase but was much less powerful than physostigmine and neostigmine in this respect. HC-15 inhibited acetylcholine (ACh) systhesis by mitochondrial (P 2) fractions of guinea-pig cerebral cortex suspended in Tris buffer but had no effect on ACh synthesis by P 2 fractions homogenized in Triton X-100 where the membranes surrounding the choline acetyltransferase (ChAc) enzyme are broken down. HC-15 therefore appears to inhibit ACh synthesis in a similar manner to HC-3 by preventing choline transport to the intracellular sites of acetylation. In the absence of choline HC-15 and HC-3 were acetylated by ChAc. HC-3 has a higher rate of acetylation than HC-15 and this effect parallels the greater activity of HC-3 on neuromuscular transmission. The possibility is suggested that the pre-junctional blocking action of both HC-15 and HC-3 may be in part due to their incorporation into cholinergic nerve endings and their subsequent release as false inactive neurotransmitters.