Formation of a piperidinium derivative from N-(5'-chloropentyl)-N-methylaminoaceto-2,6-xylidide in relation to the sustained local anaesthetic action on the sciatic nerve of the guinea-pig in vivo.

Abstract

THE possibility of using the intramolecular alkylation reaction of tertiary ω-haloalkylamines (Fig. 1) to overcome the cell membrane barrier to cyclic quaternary ammonium compounds seems to have been almost entirely overlooked. Some pharmacological applications of this principle have already been studied1–3 and we feel that the possibility of obtaining local anaesthetic agents4 may be of therapeutic interest. The nerve sheaths and membranes hinder the penetration of quaternary ammonium compounds5, but tertiary amines in their base form are able to pass6. Thus, a tertiary haloalkylamine (I in Fig. 1) should be able to cross the barriers, and, because of its capacity to cyclize, the corresponding cyclic quaternary ammonium derivative (II) would be expected to be formed at least to some extent at the sites for blockade of nerve excitation. The barriers to outward diffusion of the quaternary compound formed are probably the same as for the inward movement, so that very slow disappearance can be expected. Accordingly, if the quaternary derivative has a local anaesthetic action, this would probably be of long duration. Our observation that tertiary haloalkylamine derivatives closely related to lidocaine have a long term anaesthetic effect4 supports this hypothesis. It would be valuable, however, to try to relate the local Q XCH3 JH3 -NHCOCH2N(CH2)5CI VCH3 I 'CH3 jJrX . -NHC0CH2N 4-Ct CH3 *˜ II anaesthetic effect in vivo with the amount of (I) and of the piperidinium derivative (II) formed in the nerves. One compound, N-(5 '-chloropentyl)-N-methylaminoaceto-2,6-xyli-dide (I in Fig. 1), tritium-labelled in the 1'-position (specific activity 10 mCi/mmol), was therefore selected for the following experiments.