SYNTHETIC CURARE-LIKE AGENTS WHICH ARE REVERSIBLE BY TENSILON

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

A series of 27 bis-quaternary bipiperidine derivatives have been assayed for curare-like activity. The replacement of alkyl radicals on the nitrogen atoms by aromatic radicals converted Tensilon-irreversible agents of the decamethonium type to Tensilon-reversible agents of the tubocurarine type. The highest potency in various species was reached in compound Ro 2-4377, 4,4'-ethylenebis[l-(p-nitrophenethyl)-1-methylpiperidinium bromide]. Besides being antagonized by Tensilon (3-hydroxyphenyldimethylethylammonium chloride), Ro 2-4377 had relatively weak blood pressure effects and ganglionic blocking action, but it had relatively strong vagolytic action.

In the nitrobenzyl substituted series, maximal potency in cats was reached in compound Ho 2-3799, 4,4'-ethylene bis[1-(p-nitrobenzyl)-1-methyl-piperidinium bromide], which also has eight carbon atoms between the nitrogen atoms. The compounds having various substituents on the nitrogen atoms had a decreasing order of potency as follows: nitrophenethyl, nitrobenzyl, cyanobenzyl, carbamylbenzyl, acetylbenzyl, phenethyl, carbethoxybenzyl, methylsulfonylbenzyl, methylmercaptobenzyl, benzyl and phenyl propyl.