title: Synthesis and biological evaluation of novel hybrids of highly potent and selective α4β2-Nicotinic acetylcholine receptor (nAChR) partial agonists.
abstract: We previously reported the cyclopropylpyridine and isoxazolylpyridine ether scaffolds to be versatile building blocks for creating potent α4β2 nicotinic acetylcholine receptor (nAChR) partial agonists with excellent selectivity over the α3β4 subtype. In our continued efforts to develop therapeutic nicotinic ligands, seven novel hybrid compounds were rationally designed, synthesized, and evaluated in [3H]epibatidine binding competition studies. Incorporation of a cyclopropane- or isoxazole-containing side chain onto the 5-position of 1-(pyridin-3-yl)-1,4-diazepane or 2-(pyridin-3-yl)-2,5-diazabicyclo[2.2.1]heptane led to highly potent and selective α4β2* nAChR partial agonists with Kivalues of 0.5-51.4 nM for α4β2 and negligible affinities for α3β4 and α7. Moreover, compounds 21, 25, and 30 maintained the functional profiles (EC50and IC50values of 15-50 nM) of the parent azetidine-containing compounds 3 and 4 in the86Rb+ion flux assays. In vivo efficacy of the most promising compound 21 was confirmed in the mouse SmartCube®platform and classical forced swim tests, supporting the potential use of α4β2 partial agonists for treatment of depression.
authors.affiliation: Department of Medicinal Chemistry and Pharmacognosy, University of Illinois at Chicago, 833 South Wood Street, Chicago, IL 60612, United States; Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, 500 Dongchuan Road, Shanghai 200241, China.
authors.forename: Han-Kun
authors.initials: HK
authors.lastname: Zhang
authors.affiliation: Division of Neurobiology, Barrow Neurological Institute, 350 West Thomas Road, Phoenix, AZ 85013, United States.
authors.forename: J Brek
authors.initials: JB
authors.lastname: Eaton
authors.affiliation: PsychoGenics, Inc., 765 Old Saw Mill River Road, Tarrytown, NY 10591, United States.
authors.forename: Allison
authors.initials: A
authors.lastname: Fedolak
authors.affiliation: Department of Medicinal Chemistry and Pharmacognosy, University of Illinois at Chicago, 833 South Wood Street, Chicago, IL 60612, United States.
authors.forename: Hendra
authors.initials: H
authors.lastname: Gunosewoyo
authors.affiliation: Department of Medicinal Chemistry and Pharmacognosy, University of Illinois at Chicago, 833 South Wood Street, Chicago, IL 60612, United States.
authors.forename: Oluseye K
authors.initials: OK
authors.lastname: Onajole
authors.affiliation: PsychoGenics, Inc., 765 Old Saw Mill River Road, Tarrytown, NY 10591, United States.
authors.forename: Dani
authors.initials: D
authors.lastname: Brunner
authors.affiliation: Division of Neurobiology, Barrow Neurological Institute, 350 West Thomas Road, Phoenix, AZ 85013, United States.
authors.forename: Ronald J
authors.initials: RJ
authors.lastname: Lukas
authors.affiliation: Department of Medicinal Chemistry and Pharmacognosy, University of Illinois at Chicago, 833 South Wood Street, Chicago, IL 60612, United States; Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, 3663 North Zhongshan Road, Shanghai 200062, China. Electronic address: lfyu@sat.ecnu.edu.cn.
authors.forename: Li-Fang
authors.initials: LF
authors.lastname: Yu
authors.affiliation: Department of Medicinal Chemistry and Pharmacognosy, University of Illinois at Chicago, 833 South Wood Street, Chicago, IL 60612, United States. Electronic address: kozikowa@uic.edu.
authors.forename: Alan P
authors.initials: AP
authors.lastname: Kozikowski
mesh_terms: D000818:Animals; D001519:Behavior / Q000187:drug effects; D003863:Depression / Q000188:drug therapy; D020128:Inhibitory Concentration 50; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D015394:Molecular Structure; D018722:Nicotinic Agonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D011978:Receptors, Nicotinic / Q000737:chemistry / Q000378:metabolism; D013550:Swimming; D000068580:Varenicline / Q000737:chemistry / Q000494:pharmacology
chemical_list: D018722:Nicotinic Agonists; D011978:Receptors, Nicotinic; C403531:nicotinic receptor alpha4beta2; D000068580:Varenicline
keywords: Antidepressant-like effects; Hybrids; Partial agonists; α4β2-nAChRs