Structure and conformation of the muscarinic agonists 3-(3-amino-1,2,4-oxadiazol-5-yl)-1-azabicyclo[2.2.2]octane and 1,2,5,6-tetrahydro-1-methyl-3-pyridinecarboxaldehyde oxime and related tertiary amine, quaternary ammonium and sulfonium analogues

Abstract

A model, based on the crystal structure determinations, Cambridge Structural Database statistics and molecular mechanics calculations, is presented in which the muscarinic agonists L660863, Org 31956, 1-azabicyclo[2.2.2]octane-3-carboxylic acid methyl ester, arecoline, sulfonium-arecoline, sulfonium-isoarecoline and N-methylisoarecoline are matched. A common interaction mode for these reverse ester bioisosteres of acetylcholine is found. The low muscarinic activity of N-methylarecoline and isoarecoline can also be explained using this model