Design, synthesis and muscarinic activity of deoxamuscarine-related derivatives

The deoxamuscarine analogs 4-6 were synthesized and their biological profiles at muscarinic subtypes were assessed by functional experiments in isolated guinea pig left atria (M2) and ileum (M3), and rabbit vas deferens (M4). The muscarinic receptor potency, affinity and relative efficacy were determined as well and compared to those estimated for deoxamuscarine. The hydroxy group of deoxamuscarine was replaced by an oxime moiety, affording compound 4 that was a full agonist in all functional assay. Beckmann rearrangement of c-4-methyl-3-oxime-r-1-N,N-dimethylaminomethylcyclopentane gave only one of the possible lactam isomers (r-4-(dimethylamino)methyl-c-6-methyl-2-piperidinone) and the corresponding methiodide 5 was a full agonist. Oxime 4 and piperidinone 5 represent useful leads for the design of new muscarinic ligands.