title: The potent and selective α4β2*/α6*-nicotinic acetylcholine receptor partial agonist 2-[5-[5-((S)Azetidin-2-ylmethoxy)-3-pyridinyl]-3-isoxazolyl]ethanol demonstrates antidepressive-like behavior in animal models and a favorable ADME-tox profile.
abstract: Preclinical and clinical studies demonstrated that the inhibition of cholinergic supersensitivity through nicotinic antagonists and partial agonists can be used successfully to treat depressed patients, especially those who are poor responders to selective serotonin reuptake inhibitors (SSRIs). In our effort to develop novel antidepressant drugs, LF-3-88 was identified as a potent nicotinic acetylcholine receptor (nAChR) partial agonist with subnanomolar to nanomolar affinities for β2-containing nAChRs (α2β2, α3β2, α4β2, and α4β2*) and superior selectivity away from α3β4 - (K i > 10(4) nmol/L) and α7-nAChRs (K i > 10(4) nmol/L) as well as 51 other central nervous system (CNS)-related neurotransmitter receptors and transporters. Functional activities at different nAChR subtypes were characterized utilizing (86)Rb(+) ion efflux assays, two-electrode voltage-clamp (TEVC) recording in oocytes, and whole-cell current recording measurements. In mouse models, administration of LF-3-88 resulted in antidepressive-like behavioral signatures 15 min post injection in the SmartCube® test (5 and 10 mg/kg, i.p.; about 45-min session), decreased immobility in the forced swim test (1-3 mg/kg, i.p.; 1-10 mg/kg, p.o.; 30 min pretreatment, 6-min trial), and decreased latency to approach food in the novelty-suppressed feeding test after 29 days chronic administration once daily (5 mg/kg but not 10 mg/kg, p.o.; 15-min trial). In addition, LF-3-88 exhibited a favorable profile in pharmacokinetic/ADME-Tox (absorption, distribution, metabolism, excretion, and toxicity) assays. This compound was also shown to cause no mortality in wild-type Balb/CJ mice when tested at 300 mg/kg. These results further support the potential of potent and selective nicotinic partial agonists for use in the treatment of depression.
authors.affiliation: Department of Medicinal Chemistry and Pharmacognosy, University of Illinois at Chicago 833 South Wood Street, Chicago, Illinois, 60612 ; Institute of Drug Design and Development, Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, East China Normal University 3663 North Zhongshan Road, Shanghai, 200062, China.
authors.forename: Li-Fang
authors.initials: LF
authors.lastname: Yu
authors.affiliation: Division of Neurobiology, Barrow Neurological Institute 350 West Thomas Road, Phoenix, Arizona, 85013.
authors.forename: J
authors.initials: J
authors.lastname: Brek Eaton
authors.affiliation: Department of Medicinal Chemistry and Pharmacognosy, University of Illinois at Chicago 833 South Wood Street, Chicago, Illinois, 60612 ; 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: PsychoGenics, Inc. 765 Old Saw Mill River Road, Tarrytown, New York, 10591.
authors.forename: Emily
authors.initials: E
authors.lastname: Sabath
authors.affiliation: PsychoGenics, Inc. 765 Old Saw Mill River Road, Tarrytown, New York, 10591.
authors.forename: Taleen
authors.initials: T
authors.lastname: Hanania
authors.affiliation: Department of Medicinal Chemistry and Pharmacognosy, University of Illinois at Chicago 833 South Wood Street, Chicago, Illinois, 60612.
authors.forename: Guan-Nan
authors.initials: GN
authors.lastname: Li
authors.affiliation: Department of Medicinal Chemistry and Pharmacognosy, University of Illinois at Chicago 833 South Wood Street, Chicago, Illinois, 60612.
authors.forename: Richard B
authors.initials: RB
authors.lastname: van Breemen
authors.affiliation: Division of Neurobiology, Barrow Neurological Institute 350 West Thomas Road, Phoenix, Arizona, 85013.
authors.forename: Paul
authors.initials: P
authors.lastname: Whiteaker
authors.affiliation: Division of Neurobiology, Barrow Neurological Institute 350 West Thomas Road, Phoenix, Arizona, 85013 ; Division of Neurology, Barrow Neurological Institute 350 West Thomas Road, Phoenix, Arizona, 85013.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Liu
authors.affiliation: Division of Neurology, Barrow Neurological Institute 350 West Thomas Road, Phoenix, Arizona, 85013.
authors.forename: Jie
authors.initials: J
authors.lastname: Wu
authors.affiliation: Division of Neurobiology, Barrow Neurological Institute 350 West Thomas Road, Phoenix, Arizona, 85013.
authors.forename: Yong-Chang
authors.initials: YC
authors.lastname: Chang
authors.affiliation: Division of Neurobiology, Barrow Neurological Institute 350 West Thomas Road, Phoenix, Arizona, 85013.
authors.forename: Ronald J
authors.initials: RJ
authors.lastname: Lukas
authors.affiliation: PsychoGenics, Inc. 765 Old Saw Mill River Road, Tarrytown, New York, 10591 ; Department of Psychiatry, Columbia University, NYSPI 1051 Riverside Drive, New York, New York, 10032.
authors.forename: Dani
authors.initials: D
authors.lastname: Brunner
authors.affiliation: Department of Medicinal Chemistry and Pharmacognosy, University of Illinois at Chicago 833 South Wood Street, Chicago, Illinois, 60612.
authors.forename: Alan P
authors.initials: AP
authors.lastname: Kozikowski
keywords: Antidepressive-like behavior; nicotinic acetylcholine receptor; partial agonist; selectivity