1. Two metabolites of radioactively labelled guanethidine were isolated from rabbit and pig liver homogenates by ion-exchange chromatography on a sulphonic acid resin. 2. One of the metabolites was eluted from the column with ammonia and identified as 2-(6-carboxyhexylamino)ethylguanidine on the basis of the elemental analysis, i.r. spectrum and pH titration curve of the pure compound, and the observed partial loss of tritium for ring-labelled guanethidine during the formation of this metabolite. 3. This identification was confirmed by synthesis. 4. 2-(6-Carboxyhexylamino)ethylguanidine underwent ring-closure in hot alkaline solution to 1-(6-carboxyhexyl)-2-iminoimidazolidine. 5. The other metabolite of guanethidine was eluted from the ion-exchange column with 6m-hydrochloric acid along with the unchanged drug. It was purified by countercurrent distribution and shown to be identical with synthetic guanethidine N-oxide. 6. The two metabolites and the product of ring-closure had less than one-tenth of the antihypertensive activity of guanethidine in the renal-hypertensive rat and are unlikely to contribute to the pharmacological properties of the drug.
A further series of linear hexamethylene‐NNN‐trisonium compounds has been synthesised and tested for neuromuscular blocking activity. In the alkyl‐substituted derivatives, at least one Et is required for significant potency in mammals. Apart from the Et2Bun and EtBu2n compounds, larger alkyl substituents lower potency. High potency in mammals requires at least two Et groups on the terminal nitrogens, if the third group is not Me. Only weak activity was shown by the morpholino‐deriatives but the fowl was highly sensitive towards the piperidino‐ and tetrahydro‐papaverino‐compounds. The results are discussed.
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