The Potent And Selective Î±4Î²2*/Î±6*-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
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 Î²2-containing nAChRs (Î±2Î²2, Î±3Î²2, Î±4Î²2, and Î±4Î²2*) and superior selectivity away from Î±3Î²4Â âˆ’Â (K i Â >Â 10 4 Â nmol/L) and Î±7-nAChRs (K i Â >Â 10 4 Â 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 15Â min post injection in the SmartCube Â® test (5 and 10Â mg/kg, i.p.; about 45-min session), decreased immobility in the forced swim test (1â€“3Â mg/kg, i.p.; 1â€“10Â mg/kg, p.o.; 30Â min pretreatment, 6-min trial), and decreased latency to approach food in the novelty-suppressed feeding test after 29Â days chronic administration once daily (5Â mg/kg but not 10Â 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 300Â mg/kg. These results further support the potential of potent and selective nicotinic partial agonists for use in the treatment of depression.
Pharmacology Research and Perspectives
Digital Object Identifier (DOI)
Yu, Li Fang; Eaton, J. Brek; Zhang, Han Kun; Sabath, Emily; Hanania, Taleen; Li, Guan Nan; van Breemen, Richard B.; Whiteaker, Paul; Liu, Qiang; Wu, Jie; Chang, Yong; Lukas, Ronald J.; Brunner, Dani; and Kozikowski, Alan P., "The Potent And Selective Î±4Î²2*/Î±6*-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" (2014). Translational Neuroscience. 472.