Modifications to five-substituted 3,3-diethyl-4,5-dihydro-2(3H)- Furanones en route to novel muscarinic receptor ligands

Lead lactone-based ligands with modest affinity for muscarinic receptors were modified based on structure- activity relationship data in the literature to provide a new series of 5-substituted 4,5-dihydro-2(3H)-furanones. The modifications included the addition of various nitrogencontaining heterocycles attached to substituted and unsubstituted aromatic rings. The target compounds were synthesized in modest yields and evaluated in preliminary muscarinic binding assays. A lactone-based ligand containing a diphenylmethylpiperazine moiety was identified as a nonselective muscarinic ligand with IC50 of 340 nM. The design of future ligands will be based, in part, on structure-activity data reported herein.