An account is given of the results obtained with a number of p‐aminopbenoxyalkanes which were examined for activity against Schistosoma mansoni in mice and for the presence of retinotoxicity in cats. The first compound to be found active, 1: 5‐di(p‐aminophenoxy)‐pentane dihydrochloride (M & B 968A), was modified in a variety of ways in an attempt to increase its activity and to eliminate its ocular effects. It was found that a p‐aminophenoxyalkyl group was common to all the active compounds, but that the rest of the molecule could be any of several different groups, including alkoxy, phenoxy, and phenyl groups, without diminishing the activity. Although at least one p‐aminophenoxyalkyl group was essential for schistosomicidal activity, ocular toxicity was also shown by a p‐aminophenylalkyl derivative in which the ether linkage was absent.

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Speculation on the relationship of pharmacological activity to chemical structure is a fascinating occupation, though a complex one. An apparently small alteration in molecular configuration may profoundly change the actions of a compound; a well-known example of this is the change in neuromuscular blocking activity brought about by the replacement of methyl by ethyl groups in quaternary ammonium ions (Ing, 1936). In a preceding paper (Wien and Mason, 1951) we found that the ability of hexamethonium to paralyse autonomic ganglia was influenced by the replacement of methyl by ethyl groups on the quaternary nitrogen atoms, and we have now extended our observations to a more systematic study of the tetra-to the heptamethylene members in this alkamethonium series, as well as to several other quaternary ammonium compounds. METHODSThe methods were the same as those described previously (Wien and Mason, 1951) for determining the paralysing effects of substances on transmission through the superior cervical ganglion of the cat; on the peristaltic reflex of the isolated guinea-pig intestine; and on transmission at the neuromuscular junction by the phrenic nerve-diaphragm preparation of the rabbit. Each result in Table I was the mean of several, at least two, experiments on each test object, permitting several comparisons, but no statistical analysis was attempted. In the experiments on the nictitating membrane care was taken to space the injections far enough apart (15 to 20 minutes) to prevent sub-threshold amounts of a previous injection affecting a later one; the order of giving the compound to be tested and the standard for comparison was varied as a further safeguard. Toxicity estimations were determined intravenously in mice.Compounds.-We examined sixteen polymethylene bis-trialkylammonium dibromides of general formula (I), where n=4, 5, 6, or 7, and R=R'=R"=Me, or R=R' =Me and R"=Et, or R=Me and R'=R"=Et, or R =R'=R"=Et. They were all prepared by our colleagues (Barber and Gaimster, 1952).We also examined tetraethylammonium, triethylmethylammonium, diethyldimethylammonium, ethyltrimethylammonium, and tetramethylammonium bromides.The compound y-phenoxypropyltriethylammonium iodide was kindly supplied by Professor

Pempidine (1: 2: 2: 6: 6-pentamethylpiperidine) is a long-acting ganglion-blocking compound which is effective by mouth. By intravenous injection it has a similar potency to hexamethonium on the preganglionically stimulated nictitating membrane of the cat. The compound blocks the effects of intravenous nicotine and of peripheral vagal stimulation on the blood pressure; it also causes dilatation of the pupil after removal of the sympathetic innervation. On the guinea-pig ileum, the predominant effect of the compound is to inhibit nicotine contractions. Pempidine is well absorbed from the gastro-intestinal tract as judged by (a) the low ratio (6.9) of oral to intravenous toxicities, (b) the rapid development of mydriasis in mice after oral administration of small doses, and (c) the rapid onset of hypotension when the compound is injected directly into the duodenum of anaesthetized cats. Other actions include neuromuscular paralysis of curare-like type when large doses of the compound are injected intravenously and central effects such as tremors which occur with near toxic doses. In cats with a low blood pressure, large intravenous doses have a slight pressor action.