Physical and Pharmacological Properties of an Irreversible Local Anesthetic

A systematic investigation of a new class of ultralong-acting local anesthetic was undertaken to determine the active pharmacophore. The thermodynamic constants for the solvolvsis of the aziridinium ion (E_a, ΔH^∗, ΔS^∗) compared favorably with those reported in the literature for other aziridinium type compounds. 2-[(2-Chloro-ethyl)methylamino]ethyl 4-ethoxybenzoate-HCl upon neutralization in a physiological buffered solution blocked irreversibly the indirectly elicited twitch of the rat phrenic nerve-diaphragm preparation without altering either nerve or muscle excitability, suggesting a selective action at the neuromuscular junction at 0.2% and at an exposure time of 30 min. At 0.5%, this compound upon neutralization blocked axonal conduction of the sciatic neree of the frog irreversibly whereas comparable blockade by procaine (1%,) or lidocaine (2%) of this preparation was fully reversible upon washing. It is proposed that the aziridinium ion forms an irreversible bond with a tissue “acceptor” and the stability of this ion determines the effectiveness of drug action.