Similarities between active sites of acetylcholine receptor and acetylcholinesterase tested with quinolinium ions.

Abstract

Previous results obtained with inhibitors of ACh [acetylchollnesterase] esterase had offered evidence that a quaternary N compound, having a hydroxyl group at a distance of about 5 A from the N, forms a H bond with a basic atom, probably the O of serine, in the esteratic site, thereby strongly increasing the binding. When a series of isomeric 1-methyl-hydroxy-quinolinium ions were tested as inhibitors of the ACh receptors using the intact electroplax, evidence for hydrogen bond formation between the receptor and 1-methyl-7-hydroxyquinolinium was found. The presence of the hydroxyl group increased the inhibitory strength of the this compound about 110-fold, comparable to the effect previously observed with the corresponding enzyme inhibitor and equivalent to a decrease in the free energy of binding of about 3 kcal/mole. The hydroxyl group of 1-methyl-7-hydroxyquinollnium is also at a distance of about 5 A from the quaternary nitrogen, and the 7-hydroxyqulnolinium is the best inhibitor found. The intramolecular distance thus seems to be an Important factor in the reaction with the receptor, just as was previously found with the ACh esterase-catalyzed hydrolysis of acetoxyqulnollnium isomers.