The neuromuscular blocking action of a series of bicyclic bis‐onium esters

Abstract

, C.J 1. Thirteen bicyclic dicholine esters have been tested on mammalian and avian skeletal muscle preparations. 2. One of the compounds exhibited depolarizing activity in all the preparations. 3. Three of the compounds exhibited depolarizing or dual-blocking activity in avian and denervated mammalian preparations, but exhibited non-depolarizing blocking activity in innervated mammalian preparations. 4. The remaining compounds exhibited non-depolarizing blocking activity with evidence of an additional facilitatory action. 5. The activity exhibited was dependent upon the onium substituents and the structure of the bicycic ring. 6. All the compounds exhibited a choline-reversible block in the rapidly stimulated rat diaphragm preparation and six of them exhibited a secondary choline-reversible block of the rapidly stimulated cat tibialis anterior muscle.Several dicholine esters of a, w dicarboxylic acids containing cyclic structures have been synthesized and tested with the aim of producing a potent short-acting muscle relaxant without the depolarizing activity of suxamethonium (for reviews, see Bovet, 1951Bovet, , 1959Brucke, 1956 Koch & Kotlan (1965). The formulae of the compounds are shown in Table 1. MethodsThe compounds were tested on the following preparations.(a) The tibialis anterior muscles of cats anaesthetized with chloralose (80 mg/kg, injected intraperitoneally). Maximal twitches of a tibialis anterior muscle were elicited once every 10 sec by rectangular pulses (50 lisec duration) applied to the sciatic nerve. The strength of the shocks was about twice that required to evoke a maximal twitch. In some experiments maximal twitches of both tibialis anterior

Neuromuscular blocking activity of a new series of quaternary N‐substituted choline esters

“…Since the compound is hydrolysed, this would indicate that the second phase of the block is primarily due to triethylcholine. This contrasts with the results of Marshall (1968) and Dowd et al (1968) with other esters, where the second phase of the block was attributed to the entire compound. A dose of 30-60 mg/kg of compound 11 would release 20-40 mg/kg of triethylcholine on complete hydrolysis.…”

“…The most potent compounds in these early reports were esters of choline, which were depolarizing agents. More recently (Brittain, Collier & D'Arcy, 1961 ;Dowd et al, 1968 ;Marshall, 1968) attempts have been made to produce esters which block by non-depolarizing mechanisms. The duration of action of many of these compounds has been short, but the potency has generally been low.…”

“…The neuromuscular blocking action of several ester compounds depends largely on the nature of the choline moiety (Marshall, 1968;Dowd, Jennings, Marshall & Tracy, 1968). The pharmacology of triethylcholine and other analogues of choline has been studied by Bowman & Rand (1961, 1962 and Bowman, Hemsworth & Rand (1967).…”

Nicotinic stimulant action of some tolyl and xylyl analogues of 1,1‐dimethyl‐4‐phenylpiperazinium (DMPP)

“…parison with suxamethonium, which acts as a pure agonist on this preparation (Marshall, 1968). Log dose-response curves for all the compounds are shown in Fig.…”