Homologation as a lead modification approach en route to a series of lactone-based muscarinic ligands

Previous work identified the lactone ring as a useful scaffold for the design of muscarinic ligands and reported a lactone-based ligand with an IC₅₀ of 340 nM. Using homologation as a lead modification approach, a new series of lactone-based compounds have been designed, synthesized, and screened in muscarinic binding assays. The approach provided a series of compounds with improved % inhibition values and identified the highest affinity lactone-based ligand reported to date. The results of these efforts and the structure–activity relationship for this series of lactones-based ligands are discussed.