1 The guinea-pig isolated ileum has been used to estimate the ability of substituted phenylalkylonium
salts (related to
nicotine) to stimulate or block receptors in ganglia. The effects of
hexamethonium were used to indicate which were the most specific
ganglion stimulants; these were tested on the blood-pressure of pithed rats and for neuromuscular blocking activity on the rat diaphragm preparation.2m-Hydroxyphenylpropyltrimethylammonium and
3,4-dihydroxyphenethyltrimethylammonium (
coryneine, ;
quaternary dopamine') were the most active and specific
ganglion stimulants but their usefulness in vivo may be limited by their neuromuscular blocking activity. The analogous tertiary compounds are being investigated.3 The affinities of substances which were blocking agents at ganglionic receptors were measured on the isolated ileum with m-hydroxyphenylpropyltrimethylammonium as agonist. The affinities of selected compounds for postganglionic receptors were measured in experiments on the ileum in the presence of
hexamethonium and with
carbachol as agonist. Some of the compounds were tested for neuromuscular blocking activity on the rat diaphragm.4 Phenylbutyldiethylamine had
ganglion-blocking activity greater than
pempidine and little postganglionic blocking or neuromuscular blocking activity. Its triethylammonium analogue had higher
ganglion-blocking activity but had appreciable neuromuscular blocking activity.5 The aromatic ring system is not essential either for activity or affinity and the effects of substituents are not related to their effects on electron distribution. Stimulant activity is enhanced only by
hydroxyl or amino groups in suitable positions; it is not improved by the presence of rigid features (double or triple bonds or a
cyclopropane ring) in the side chain. Affinity is slightly increased by chloro or bromo groups in suitable positions but the unsubstituted compounds are among those with the highest affinity. Substituents have similar effects on affinity for postganglionic receptors, though for these receptors the compounds mostly have only about one-tenth of their affinity for ganglionic receptors.