A comparison of the neuromuscular and autonomic blocking activities of (+)-tubocurarine and its N-methyl and O,O,N-trimethyl analogues

Abstract

(+)-Tubocurarine was compared to its methyl analogues (+)-N-methyltubocurarine and (+)-O,O,N-trimethyltubocurarine for differences in neuromuscular and autonomic blocking activities. On the cat soleus muscle O,O,N-trimethyltubocurarine had the highest neuromuscular blocking activity, tubocurarine the lowest and N-methyltubocurarine was intermediate. The ganglion blocking activities of tubocurarine and N-methyltubocurarine were equal, but O,O,N-trimethyltubocurarine was less active. Vagolytic activity was determined in the cat and all three compounds were equipotent, but only O,O,N-trimethyltubocurarine blocked the bradycardial response of acetyl-β-methylcholine. It is suggested that tubocurarine and N-methyltubocurarine block parasympathetic vagal ganglia and only O,O,N-trimethyltubocurarine blocks cardiac muscarinic receptors. The neuromuscular blocking activities were also compared by determination of pA 2 values, against carbachol, on the isolated chick biventer cervicis muscle. These results indicated competitive antagonism by all three antagonists and showed that activities were different in different species. It is concluded that previous workers overestimated the increased neuromuscular blocking activity due to O-methylation of tubocurarine.