STRUCTURE-ACTIVITY RELATIONSHIPS AMONG A SERIES OF ACETYLENIC CARBAMATES RELATED TO McN-A-343

¹ Department of Pharmacology, Research Division, McNeil Laboratorie, Incorporated, Fort Washington, Pennsylvania

A study was undertaken of the relation between autonomic effects and chemical structure among a cries of compounds related to McN-A-343, 4-(m-chlorophenylcarbamoyloxy)-2-butynyltrimethylammonium chloride. A shift of the chlorine atom from position 3 to position 4 produces a 3-fold enhancement of ganglionic stimulant activity qualitatively similar to that induced by McN-A-343, i.e., it is readily antagonized by atropine. Shift of the chlorine atom to position 2 causes a decrease to [unknown] the activity of McN-A-343. m-Trifluoro or 2.5-dichloro substitution also reduces activity, as does saturation of the acetylenic group to an ethylenic group. The fully saturated material is devoid of ganglionic stimulant effects, producing instead depolarizing-type neuromuscular blockade; this substance is approximately [unknown] to [unknown] as active as decamethonium. Only the quaternary ammonium compounds display autonomic effects of consequence. The triethylammonium substituted analog displays a mixture of short-acting ganglionic blockade (hexamethoniumlike) and atropine-like effects. Removal of the chlorophenyl portion of this molecule results in the formation of compounds which display marked cholinomimetic activity. These range in potency from [unknown] to times that of acetylcholine.

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