title: Discovery of highly potent and selective α4β2-nicotinic acetylcholine receptor (nAChR) partial agonists containing an isoxazolylpyridine ether scaffold that demonstrate antidepressant-like activity. Part II.
abstract: In our continued efforts to develop α4β2-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.
authors.affiliation: Drug Discovery Program, Department of Medicinal Chemistry and Pharmacognosy, University of Illinois at Chicago, 833 South Wood Street, Chicago, Illinois 60612, USA.
authors.forename: Li-Fang
authors.initials: LF
authors.lastname: Yu
authors.forename: J Brek
authors.initials: JB
authors.lastname: Eaton
authors.forename: Allison
authors.initials: A
authors.lastname: Fedolak
authors.forename: Han-Kun
authors.initials: HK
authors.lastname: Zhang
authors.forename: Taleen
authors.initials: T
authors.lastname: Hanania
authors.forename: Dani
authors.initials: D
authors.lastname: Brunner
authors.forename: Ronald J
authors.initials: RJ
authors.lastname: Lukas
authors.forename: Alan P
authors.initials: AP
authors.lastname: Kozikowski
mesh_terms: D000818:Animals; D000928:Antidepressive Agents / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D007555:Isoxazoles / Q000737:chemistry*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009043:Motor Activity / Q000187:drug effects; D009447:Neuroblastoma / Q000188:drug therapy*; D018722:Nicotinic Agonists / Q000737:chemistry / Q000494:pharmacology*; D011485:Protein Binding; D011869:Radioligand Assay; D011978:Receptors, Nicotinic / Q000737:chemistry* / Q000378:metabolism; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013550:Swimming / Q000502:physiology*
chemical_list: D000928:Antidepressive Agents; D007555:Isoxazoles; D018722:Nicotinic Agonists; D011978:Receptors, Nicotinic; C403531:nicotinic receptor alpha4beta2