The pharmacological actions of some polymethylene-bis-(hydroxyethyl)-dimethyl-ammonium compounds on cholinergic transmission.

Some polymethylene-bis-(hydroxyethyl)-dimethyl-ammonium (dicholine) compounds containing from 7 to 10 methylene groups between the quaternary nitrogen atoms, have been studied for activity at various sites of cholinergic transmission. The post-junctional activity of the compounds was investigated on the frog rectus abdominis muscle. Small doses of C8-, C9-, and C10-dicholine potentiated ACh contractions, however larger doses of all the dicholine compounds blocked the nicotinic receptor sites of the frog rectus muscle. The dicholine compounds blocked neuromuscular transmission in the rat phrenic nerve diaphragm. These actions at the rat neuromuscular junction are compared with the purely post-junctional actions on the frog rectus muscle. Although the compounds exert anticholinesterase activity in vitro it is suggested that this effect plays little part in the action of the drugs at the neuromuscular junction. It is concluded that the dicholine compounds have both pre- and post-junctional activity at the neuromuscular junction. The dicholine compounds are acetylated at varying rates by partially purified choline acetyltransferase (ChAc) although all are acetylated less readily than choline. The rate of acetylation of the dicholine compounds by ChAc parallels their activity in blocking neuromuscular transmission and it is suggested that other quaternary ammonium compounds containing hydroxyl or hydroxyethyl groupings may be acetylated by ChAc and this may affect their blocking action at the neuromuscular junction.