Abstract
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 nitrogen-containing 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.
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Acknowledgments
The authors are grateful to Temple University (D. J. C.; Grant-in-Aid of Research) and the Dean’s office, Temple University School of Pharmacy, for generous financial support and to Dr. Magid Abou-Gharbia and Rogelio Martinez (Moulder Center for Drug Discovery Research) for access to instrumentation and helpful discussions regarding this work. R. R. B is thankful to Dr. Schafmeister/Kavita Akula for providing the LC–MS data for test compounds.
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Bhandare, R.R., Canney, D.J. Modifications to five-substituted 3,3-diethyl-4,5-dihydro-2(3H)-furanones en route to novel muscarinic receptor ligands. Med Chem Res 20, 558–565 (2011). https://doi.org/10.1007/s00044-010-9349-7
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DOI: https://doi.org/10.1007/s00044-010-9349-7