AUTONOMIC BLOCKING COMPOUNDS. I. GANGLION BLOCKING ACTION OF SOME ALIPHATIC QUATERNARY AMMONIUM SALTS, RELATED ALKYL PIPERIDINIUM SALTS AND 1, 2, 3,4-TETRAHY-DROISOQUINOLINIUM SALTS

¹ Division of Biological Research, G. D. Searle & Co., Chicago 80, Illinois

The ganglion blocking activity of a series of aliphatic quaternary ammonium, alkylpiperidinium and 1,2,3,4-tetrahydroisoquinolinium derivatives was studied. The compounds appear to cause autonomic blockade only by ganglionic paralysis.

Among the aliphatic quaternary ammonium and piperidinium salts, ethyl substituents on the quaternary nitrogen are more effective than methyl. Introduction of an hydroxyl on the terminal carbon of an N-ethyl group has a deleterious effect on blocking activity. The introduction of a methyl (or ethyl) branch on the alkyl carbon(s) adjacent to the quaternary nitrogen results in a sharp increase in potency. This effect is not observed when methyl is introduced on other positions. In general, the piperidinium salts have the same order of activity as their aliphatic analogues. The most active members of this group, diethyldiisopropylammonium chloride and 1,1-diethyl-2,6-dimethyl piperidinium bromide are 13 and 10 times as active as tetraethylammonium bromide, on a molar basis.

Among the tetrahydroisoquinolinium salts, the substituents on the quaternary nitrogen (methyl and ethyl) do not influence the activity markedly. However, substituents on other positions of the ring system may result in marked changes in ganglionic blockade. The most active members of this series have hydroxyl or methoxyl groups at positions 6 and 7 of the unsaturated ring and a large substituent at position 1. 1-Benzyl-6,7-dihydroxy-2,2-dimethyl-1,2,3,4-tetrahydroisoquinolinium chloride is approximately ten times as active as TEA on a molar basis.