title: Chemistry, pharmacology, and behavioral studies identify chiral cyclopropanes as selective α4β2-nicotinic acetylcholine receptor partial agonists exhibiting an antidepressant profile. Part II.
abstract: A 3-pyridyl ether scaffold bearing a cyclopropane-containing side chain was recently identified in our efforts to create novel antidepressants that act as partial agonists at α4β2-nicotinic acetylcholine receptors. In this study, a systematic structure-activity relationship investigation was carried out on both the azetidine moiety present in compound 3 and its right-hand side chain, thereby discovering a variety of novel nicotinic ligands that retain bioactivity and feature improved chemical stability. The most promising compounds, 24, 26, and 30, demonstrated comparable or enhanced pharmacological profiles compared to the parent compound 4, and the N-methylpyrrolidine analogue 26 also exhibited robust antidepressant-like efficacy in the mouse forced swim test. The favorable ADMET profile and chemical stability of 26 further indicate this compound to be a promising lead as a drug candidate warranting further advancement down the drug discovery pipeline.
authors.affiliation: Department of Medicinal Chemistry and Pharmacognosy, University of Illinois at Chicago , 833 South Wood Street, Chicago, Illinois 60612, United States.
authors.forename: Han-Kun
authors.initials: HK
authors.lastname: Zhang
authors.forename: Li-Fang
authors.initials: LF
authors.lastname: Yu
authors.forename: J Brek
authors.initials: JB
authors.lastname: Eaton
authors.forename: Paul
authors.initials: P
authors.lastname: Whiteaker
authors.forename: Oluseye K
authors.initials: OK
authors.lastname: Onajole
authors.forename: Taleen
authors.initials: T
authors.lastname: Hanania
authors.forename: Daniela
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*; D001667:Binding, Competitive; D018938:Caco-2 Cells; D002460:Cell Line; D045744:Cell Line, Tumor; D003521:Cyclopropanes / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004355:Drug Stability; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D008956:Models, Chemical; D015394:Molecular Structure; D009043:Motor Activity / Q000187:drug effects; D018722:Nicotinic Agonists / Q000737:chemistry / Q000494:pharmacology*; D011869:Radioligand Assay; D051381:Rats; D011978:Receptors, Nicotinic / Q000378:metabolism*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013550:Swimming / Q000523:psychology
chemical_list: D000928:Antidepressive Agents; D003521:Cyclopropanes; D065607:Cytochrome P-450 Enzyme Inhibitors; D018722:Nicotinic Agonists; D011978:Receptors, Nicotinic; C403531:nicotinic receptor alpha4beta2; D003577:Cytochrome P-450 Enzyme System