The neuromuscular and autonomic blocking effects of azasteroids containing choline or acetylcholine fragments.

Abstract

Nine analogues of the azasteroid muscle relaxant chandonium have been tested for neuromuscular blocking activity, ganglion blocking activity, inhibitory effects on cardiac muscarinic receptors, and for effects on noradrenergic transmission. Experiments were performed in anaesthetized cats and in isolated preparations. The two bisquaternary compounds HS-626 and HS-627, choline and acetylcholine-like analogues of chandonium respectively, were approximately equipotent with chandonium as neuromuscular blocking agents in the cat, but HS-672 possessed slightly more vagal blocking action. No evidence was obtained for ganglion block. The monoquaternary analogues, HS-408 and HS-465 and two 4-aza-androstanes, (HS-522 and HS-523) were more than 100 times less active than the bisquaternary compounds as neuromuscular blocking agents, and produced vagal blockade and ganglion blockade at sub-neuromuscular blocking doses. pA2 determinations in the chick biventer cervicis muscle, the guinea-pig atria and guinea-pig ileum showed that the bisquaternary compounds chandonium, HS-626 and HS-627 were much more potent in blocking cardiac than intestinal muscarinic receptors and that HS-626 possessed the widest margin between concentrations blocking the nicotinic receptors at the neuromuscular junction and the cardiac muscarinic receptors. Evidence for the three bisquaternary compounds blocking neuronal noradrenaline reuptake was obtained only at very high concentrations. HS-626 possessed a slightly more desirable spectrum of activities than chandonium, but the degree of improvement over the parent compound is insufficient to merit extensive clinical testing.