AN INVESTIGATION OF THE MOLECULAR CONFIGURATIONS FAVORABLE FOR STIMULATION OR BLOCKADE OF THE ACETYLCHOLINE-SENSITIVE RECEPTORS OF VISCERAL ORGANS

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

1. A large variety of structurally diverse molecules are capable of reacting with the acetylcholine sensitive receptor of the heart and intestine and thereby inducing stimulation (cholinemimetic action). The most effective compounds have at least one methyl group in the cationic head and a terminal methyl group at a distance of about 7 Å. No structural elements other than C, H and N are required for this action.

2. The acetate esters of 1-methyl-3-piperidylmethanol are weak cholinemimetic agents.

3. Substitution of the terminal methane by aromatic, heterocyclic, cycloalkyl and/or an hydroxyl abolishes cholinemimetic action and the resultant molecule is an active cholinolytic agent. Evidence is presented suggesting that blockade results from the saturation of the receptor surface with inactive molecules.

4. The distance between the N and the substituted terminal methane does not appear to be critical but this distance is 4-8 Å for the most active cholinolytic agents.

5. Various derivatives of 1-methylpiperidine have cholinolytic activities of the same order of magnitude as that of atropine. It is suggested that the methylpiperidine ring is the essential part of tropine.