THE CHOLINOLYTIC ACTION OF SUBSTITUTED DIALKYLAMINOALKANES AND DIALKYLAMINOALKANOLS

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

Potent cholinolytic (anticholinergic) action has been demonstrated in a series of dialkylaminoalkanols. The methohalide salts are significantly more effective than the corresponding hydrochlorides. The presence of a hydroxy substitution on the terminal carbon contributes importantly to cholinolytic potency. In addition, the presence of an umbrella-like mass obtained by varied substitutions on the terminal carbon also contributes to this activity. Although varied, the substituents which characterize the most potent compounds suggest that there is some degree of structural specificity involved.

The results of this investigation and that of previous ones carried out in our laboratories, and discussed in this communication, suggest the following generalizations. Post-ganglionic parasympathetic fibers of the autonomic nervous system supply a single type of receptor which has the characteristics of a crevice or trough-like structure in which the active cholinolytic drug is held by electrostatic attraction to an anionic area by the cationic head and by a second point of attachment to the receptor through a hydroxy (polar) group, this latter being at a distance of 4-7 Aring; from the cationic head. The overall length of the reactive receptor surface is about 7-8 Å, measured from the anionic site.

Quaternization of the amine with a methyl- or ethylhalide increases cholinolytic potency, possibly by providing a more favorable fit to the receptor site (a near optimal stereochemical change) and/or by increasing the electrostatic charge on the nitrogen. This change in the cationic group increases toxicity but there appears to be no direct correlation between the observed cholinolytic action and the toxic effects.