Discovery Of Highly Potent And Selective Î±4Î²2-Nicotinic Acetylcholine Receptor (Nachr) Partial Agonists Containing An Isoxazolylpyridine Ether Scaffold That Demonstrate Antidepressant-Like Activity. Part II
In our continued efforts to develop Î±4Î²2-nicotinic acetylcholine receptor (nAChR) partial agonists as novel antidepressants having a unique mechanism of action, structure-activity relationship (SAR) exploration of certain isoxazolylpyridine ethers is presented. In particular, modifications to both the azetidine ring present in the starting structure 4 and its metabolically liable hydroxyl side chain substituent have been explored to improve compound druggability. The pharmacological characterization of all new compounds has been carried out using [ 3 H]epibatidine binding studies together with functional assays based on 86 Rb + ion flux measurements. We found that the deletion of the metabolically liable hydroxyl group or its replacement by a fluoromethyl group not only maintained potency and selectivity but also resulted in compounds showing antidepressant-like properties in the mouse forced swim test. These isoxazolylpyridine ethers appear to represent promising lead candidates in the design of innovative chemical tools containing reporter groups for imaging purposes and of possible therapeutics. Â© 2012 American Chemical Society.
Journal of Medicinal Chemistry
Digital Object Identifier (DOI)
Yu, Li Fang; Eaton, J. Brek; Fedolak, Allison; Zhang, Han Kun; Hanania, Taleen; Brunner, Dani; Lukas, Ronald J.; and Kozikowski, Alan P., "Discovery Of Highly Potent And Selective Î±4Î²2-Nicotinic Acetylcholine Receptor (Nachr) Partial Agonists Containing An Isoxazolylpyridine Ether Scaffold That Demonstrate Antidepressant-Like Activity. Part II" (2012). Translational Neuroscience. 206.