Enzyme inhibiting activityEnzyme inhibiting activity X 0220Novel Piperidinium and Pyridinium Agents as Water-Soluble Acetylcholinesterase Inhibitors for the Reversal of Neuromuscular Blockade. -A previously synthesized potent piperidinium containing AChE inhibitor is optimized by increasing the water solubility as well as by removing the potential problems associated with stereoisomers of the quaternary salt. The novel piperidinium and pyridinium agents contain a common dimethoxybenzothiophene core and are connected with the quaternary ammonium bearing part by propanone as the optimum linker. Compounds (I), (IIa), and (IIb) are potent AChE inhibitors and water soluble. Additionally, (IIa) reverses neuromuscular blockade. Pyridinium salt (IIc) displays excellent AChE inhibition and excellent in vitro reversal activity, but its water solubility is low. -(PALIN*, R.; CLARK, J. K.; COWLEY, P.; MUIR, A. W.; POW, E.; PROSSER, A. B.; TAYLOR, R.; ZHANG, M.-Q.; Bioorg. Med.
This study was undertaken to investigate the neuromuscular blocking profile and cardiovascular effects of Org 9487, a new aminosteroidal, non-depolarizing, neuromuscular blocking agent structurally related to vecuronium, in anaesthetized animals and in isolated muscle preparations. In in vitro functional assays of neuromuscular blocking activity, Org 9487 was between eight and 15 times less potent than vecuronium. In cats and monkeys the potency of Org 9487 was approximately one-seventh and one-twentieth, respectively, that of vecuronium. In both species, Org 9487 induced rapidly developing (onset times between 1.5 min and 1.9 min) neuromuscular paralysis, which was shorter-lasting than that of vecuronium and similar in time course to suxamethonium. The vagal: neuromuscular blocking dose ratio for Org 9487 was 3 and ganglion block was seen only at approximately 20 times the neuromuscular blocking dose. There was no evidence in the rat that Org 9487, administered at doses up to 3 mg kg-1, inhibited noradrenaline re-uptake. In anaesthetized dogs, Org 9487 (3 x 90% blocking dose) induced only relatively small and transient haemodynamic effects. The administration of clinically relevant doses of neostigmine or pyridostigmine shortened the time-course profile of Org 9487, even when administered during profound neuromuscular block. In animals, Org 9487 is a low potency, nondepolarizing neuromuscular blocking agent with a time course profile similar to that of suxamethonium. Although Org 9487 is less selective than vecuronium for the neuromuscular junction, it is unlikely to produce prohibitive cardiovascular side effects in man.
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