THE CONVERSION OF DECAMETHONIUM-LIKE AGENTS TO TENSILON-REVERSIBLE AGENTS BY AROMATIC SUBSTITUENTS

¹ Pharmacology Department, Hoffmann-La Roche Inc., Nutley 10, New Jersey

Five analogs of decamethonium containing nitrobenzyl radicals in place of methyl groups on the nitrogen atoms were found to resemble d-tubocurarine in being Tensilon-reversible. Maximal potency in cats was reached in compound Ro 2-4501, N,N'-nonamethylenebis[dimethyl(p-nitrobenzyl)ammonium bromide] dihydrate. It had about the same activity as d-tubocurarine in the cat, but was less active in the mouse, rabbit, monkey and pigeon. It was less active on sympathetic ganglia and blood pressure but equally active on the vagus endings.

Likewise, the nitrobenzyl and cyanobenzyl analogs of Mytolon chloride were Tensilon-reversible. The nitrobenzyl compound, Ro 2-4395, N,N'-(2,5-dihydro-2,5-dioxo-1,4-phenylene)bis[(3-aminopropyl)(p-nitrobenzyl)-diethylammonium chloride] dihydrate, was more active than d-tubocurarine in the cat and rabbit, equally active in the mouse and pigeon and less active in the monkey. It had lower ganglionic blocking action and blood pressure effects, but equal vagal blocking action in comparison to d-tubocurarine.

Eight analogs of succinyicholine, dipropamine and similar agents which contain the nitrobenzyl radical instead of alkyl groups on the nitrogen atoms were Tensilon-reversible. The most active compound, Ro 2-4658, ,'-(p-phenylene-dioxy)bis[diethyl(p-nitrobenzyl)propylammonium bromide] dihydrate, was stronger than d-tubocurarine in the cat, mouse and rabbit, equal in the pigeon but weaker in the monkey. The ganglionic blocking action and blood pressure effects were weaker than those of d-tubocurarine, but the vagal blocking action was stronger.

The nitrobenzyl group when substituted for alkyl groups on the nitrogen atoms of bis-quaternary ammonium compounds appears to have the property of converting Tensilon-irreversible agents of the decamethonium type to Tensilon-reversible agents of the d-tubocurarine type.