Study of cholinoreceptive membrane in sympathetic ganglion by analysis of structure-activity relationship.

Asymmetrical analogs of bistrimethylammonium salts were synthesized which had 4-6 methylene groups, one trimethylammonium cationic head and another cationic head which could be systematically altered. They were tested for their ganglion-blocking activity on the cat superior cervical sympathetic ganglion. These asymmetrical analogs were substantially more active than symmetrical ones. This fact favors the hypothesis that the two anionic sites on the cholinoreceptor surface with which bis-cation gangliolytics combined are not identical. One of these sites is assumed to be the main anionic site of the cholinoreceptor which is geometrically complementary to the trimethylammonium group of acetylcholine; the second anionic site, which is not structurally identical with the main anionic site of the cholinoreceptor, is located at a distance of 4 methylene groups. Not only the different geometry of the cationic head but hydrophobic interactions and hydrogen bonding seem to be very important for optimal binding to the second anionic site and thereby for high ganglion-blocking activity. The possible role of the second anionic site in receptor function is discussed.