Stereoselectivity of Some Muscarinic and Antimuscarinic Agents Related to Oxotremorine

Oxotremorine, N-(4-pyrrolidino-2-butynyl)-2-pyrrolidone ([1]), is a muscarinic agent equal in potency to acetylcholine (3, 7). Its extraordinary potency is surprising in view of its structural dissimilarity to other muscarinic agents. Whereas most powerful muscarinic agents possess a quaternary trimethyl ammonium group, oxotremorine is a tertiary amine with no N-methyl groups at all. Moreover, it contains an acetylenic bond at the position in the molecule where strong muscarinic agents have an oxygen atom. The structural requirements for muscarinic activity are rather specific and even slight changes in the structure lead to loss of the muscarinic activity or to a change of the type of activity from agonistic to antagonistic (4, 14). The only amino congeners which show agonistic activity of the same order of magnitude as oxotremorine are the dimethylamino ([2]) and the azetidino ([3]) analogs. Compound [3] is in fact the most potent tertiary muscarinic agent known to date (see structures on next page).