STRUCTURE AND CONFORMATION OF THE MUSCARINIC AGONISTS NO-1,2,4-OXADIAZOL-5-YL)-1-AZABICYCLO[2.2.2]OCTANE AND 2,5,6-TETRAHYDRO-1-METHYL-3-PYRIDINECARBOXALDEHYDE OXIME AND RELATED TERTIARY AMINE, QUATERNARY AMMONIUM AND SULFONIUM ANALOGS

The crystal structures of two muscarinic agonists, o-1,2,4-oxadiazol-5 -yl)-1-azabicyclo[2.2.2]-octane [L-660863, C9H14N4O, M(r) = 194.24, tr iclinic, P1BAR, a = 6.607 (1), b = 8.2157 (8), c = 9.287 (1) angstrom, alpha = 105.52 (1), beta = 93.88 (1), gamma = 91.79 (1)-degrees, V = 484.0 (1) angstrom3, Z = 2, D(x) = 1.33 g cm-3, lambda (Mo Kalpha) = 0 .71073) angstrom, mu = 0.9 cm-1, F(000) = 208, R = 0.041 for 1935 refl ections with I > 2.5sigma(I)] and ,-5,6-tetrahydro-2-methyl-3-pyridine carboxaldehyde oxime monohydrochloride [Org 31956, C7H13N2O+- Cl-, M(r ), = 176.64, triclinic, P1BAR, a = 6.843 (3), b = 6.997 (3), c = 9.837 (4) angstrom, alpha = 89.72 (3), beta = 87.78 (4), gamma = 75.69 (4)- degrees, V = 456.0 (3) angstrom, Z = 2, D(x) = 1.286 g cm-3, lambda(Mo Kalpha) = 0.71073 angstrom, mu = 3.7 cm-1, F(000) = 188, R = 0.046 fo r 2195 reflections with I > 2.5sigma(I)] have been determined. A model , based on these crystal structure determinations, Cambridge Structura l Database statistics and molecular mechanics calculations, is present ed in which the muscarinic agonists L-660863, Org 31956, I-azabicyclo[ 2.2.2]octane-3-carboxylic acid methyl ester, arecoline, sulfonium-arec oline, sulfonium-isoarecoline and N-methylisoarecoline are matched. A common interaction mode for these reverse ester bioisosteres of acetyl choline is found, provided that the different interaction geometries o f quaternary ammonium, protonated tertiary amino and sulfonium groups with a negatively charged receptor site are taken into account. The lo w muscarinic activity of N-methylarecoline and isoarecoline can also b e explained using this model. Acetylchohne cannot be fitted into this model, which suggests that the discussed compounds bind to the muscari nic receptor site in a mode that is different from that of acetylcholi ne.