3-ACETOXYQUINUCLIDINE METHIODIDE . RESOLUTION, ABSOLUTE CONFIGURATION, AND STEREOSPECIFICITY OF INTERACTION WITH ACETYLCHOLINE BINDING SITES

The general problem of the absolute conformation of receptor- and enzyme-bound quaternary muscarinic agents is briefly reviewed. Special attention is devoted to the super-muscarinic agent L(+)-cts-dioxolane (I), in which the conformation of the cationic moiety is not fixed. It is pointed out that 3-acetoxyquinuclidine methiodide has a frozen conformation about the cationic center and thus may provide a suitable conformational frame allowing a decision regarding the active conformation of the cationic part of I in the bound state. It was found that (S)-(-)-3-aretoxyquinuclidine methiodide (II) is related to (S)-(+)-β-methylaeetylcholme (III) and like the latter behaves as a good substrate for AChE. As a muscarinic agent, (S)-(-)-II has 1/600th the activity of acetylcholine (ACh). The (R)-(+) enantiomer of II was found to be inactive as a substrate for AChE, and to be 1/36,000th as active as ACh as a muscarinic agent. It was tentatively concluded that the active conformation of I in the bound state may be as shown in IV. It seems possible, therefore, that strained conformations of stimulants may be favored in the enzyme and receptor bound states. © 1969, American Chemical Society. All rights reserved.