AN INVESTIGATION OF THE STRUCTURE-ACTIVITY CORRELATIONS WITHIN A SERIES OF AMBENONIUM ANALOGS

¹ Pharmacology Section, Sterling-Winthrop Research Institute, Rensselaer, New York

Inhibition of AChE has been demonstrated with ambenonium and related compounds. The structure of the ammonium group shows highly specific requirements for optimum activity. Effective blocking agents are obtained with bis-ammoium quaternary compounds at extended lengths of about 12 Å and again at about 17 Å to 20 Å.

An extensive investigation in the albino mouse has shown that ambenonium and related compounds may cause voluntary muscle paralysis at lower doses than would be expected from a comparison with known curarizing drugs, evaluated in terms of their respective toxicities. Facilitation as well as motor paralysis (inclined screen) is most marked with compounds having distances between the terminal N centers of 12 Å or 17 Å to 20 Å.

Effective facilitatory compounds are also effective antagonists of tetraethylpyrophosphate toxicity in mice. Inasmuch as this is not observed with the potent anticholinesterase, neostigmine, it is suggested that this protection involves more than protective binding of AChE.