STEREOCHEMICAL FACTORS INVOLVED IN CHOLINOLYTIC ACTIVITY

¹ Sterling-Winthrop Research Institute, Rensselaer, New York

1 . The cholinolytic activity of three pairs of optical isomers has been determined by means of the rabbit isolated ileal segment, by blockade of carbamyl-choline induced vasodepression and salivation in anesthetized dogs and by the quantitation of mydriasis in mice.

2. Chemical methods used for the separation of the optical isomers are described. The dextro isomers were subjected to repeated recrystallization until no further change in biological activity could be detected.

3. The levo to dextro activity ratio for hyoscyamine was 1:110 to 1:250, varying somewhat in the different assay procedures. The activity ratios for the isomers of 1-cyclohexyl-1-phenyl-3-piperidinopropanol were observed to be 1:157 to more than 1:500 whereas 1-cyclohexyl-1--thienyl-3-piperidinopropanol isomers have a ratio distinctly less than the above.

4. The dextro isomers have little cholinolytic activity. They are less active than the optically inactive 1, 1-diphenyl-3-piperidinopropanol.

5. At least a three point attachment of potent cholinolytic compounds to the receptor surface is proposed. The important structures are the cationic head, a group that can be involved in hydrogen bond formation and a large cyclic substitution. An ester group in the reacting molecule is not essential.

6. Charge distribution on the receptor surface is discussed. The evidence presented suggests that the receptor surface contains an anionic site which will be associated with the solvated tertiary amino group, a positive center which will react with a properly spaced carbonyl function, a second negative center invovled in hydrogen bonding and an area of limited dimensions which can form an attachment to the cyclic portion of the molecule.