TY - JOUR T1 - OBSERVATIONS ON THE NEUROMUSCULAR BLOCKING ACTIVITY OF A SERIES OF BIS-QUATERNARY PYRIDAZINES, WITH PARTICULAR REFERENCE TO THE EFFECTS OF FREQUENCY OF STIMULATION JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 388 LP - 394 VL - 118 IS - 4 AU - R. M. Gesler AU - James O. Hoppe Y1 - 1956/12/01 UR - http://jpet.aspetjournals.org/content/118/4/388.abstract N2 - The neuromuscular bloekimig activity of a series of bis-quarternary pyridazines has been determined in the mouse, cat and rabbit. In general, the bis-quaternary salts of 3,6-bis(3-dialkylaminopropoxy) pyridazine were approximately as active or more active than d-tubocurarine, while the bis-quaternary salts of 3,6-bis(2-dialkylaminoethoxy) pyridazine were considerably less active. The behavior of Compound IV, d-tubocurarine and decamethonium in the unanesthetized cat was similar to their respective effects, in both potency and duration, in the cat sciatic-gastroenemius preparation whether stimulated at 1 per 15 seconds or at 1 per second. The effects of Compounds V and VI in the unanesthetized animal and in the nerve-muscle preparation were similar when the latter was stimulated at a I per second frequency, but were not similar when stimulated at a 1 per 15 second frequency. Anticholinesterase activity was less than 3 per cent of that of neostigmine throughout the series. No important cardiovascular effects were observed at dosage levels producing almost complete neuromuscular blockade. Compound V, 3, 6-bis(3-diethylaminopropoxy) pyridazine bis-methiodide, at doses of 0.031 to 2.0 mgm./kgm., produced a reversible neuromuscular blockade of long duration in the cat bilateral sciatic-gastrocnemius preparation stimulated maximally and indirectly at a frequency of 1 per second, but had little or no effect on the contralateral gastrocnemius so stimulated at a frequency of 1 per 15 seconds. The bis-triethyl ammonium analogue and the two bis-diethylmethyl ammonium analogues in the ethoxy series were qualitatively similar but less active, while the his-trimethyl ammonium analogue, the bis-diethyl nitrobenzyl and the bis-dimethyl nitrobenzyl ammonium analogues, as well as d-tubocurarine and decamethonium could not be so differentiated by the two frequencies of stimulation. A pharmacological basis for the inhibition of exaggerated motor activity in hypertomuic skeletal muscle conditions was discussed. The neuromuscular blocking action of Compound V suggests that it might be able to ameliorate the intensity of skeletal muscle spasm in various spastic disorders. ER -