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In our effort to develop novel antidepressant drugs, LF\u20103\u201088 was identified as a potent nicotinic acetylcholine receptor (<jats:styled-content style=\"fixed-case\">nAChR<\/jats:styled-content>) partial agonist with subnanomolar to nanomolar affinities for <jats:italic>\u03b2<\/jats:italic>2\u2010containing <jats:styled-content style=\"fixed-case\">nAChR<\/jats:styled-content>s (<jats:italic>\u03b1<\/jats:italic>2<jats:italic>\u03b2<\/jats:italic>2, <jats:italic>\u03b1<\/jats:italic>3<jats:italic>\u03b2<\/jats:italic>2, <jats:italic>\u03b1<\/jats:italic>4<jats:italic>\u03b2<\/jats:italic>2, and <jats:italic>\u03b1<\/jats:italic>4<jats:italic>\u03b2<\/jats:italic>2*) and superior selectivity away from <jats:italic>\u03b1<\/jats:italic>3<jats:italic>\u03b2<\/jats:italic>4\u00a0\u2212\u00a0(<jats:italic>K<\/jats:italic><jats:sub>i<\/jats:sub>\u00a0&gt;\u00a010<jats:sup>4<\/jats:sup>\u00a0nmol\/L) and <jats:italic>\u03b1<\/jats:italic>7\u2010<jats:styled-content style=\"fixed-case\">nAChRs<\/jats:styled-content> (<jats:italic>K<\/jats:italic><jats:sub>i<\/jats:sub>\u00a0&gt;\u00a010<jats:sup>4<\/jats:sup>\u00a0nmol\/L) as well as 51 other central nervous system (CNS)\u2010related neurotransmitter receptors and transporters. Functional activities at different <jats:styled-content style=\"fixed-case\">nAChR<\/jats:styled-content> subtypes were characterized utilizing <jats:sup>86<\/jats:sup>Rb<jats:sup>+<\/jats:sup> ion efflux assays, two\u2010electrode voltage\u2010clamp (TEVC) recording in oocytes, and whole\u2010cell current recording measurements. In mouse models, administration of LF\u20103\u201088 resulted in antidepressive\u2010like behavioral signatures 15\u00a0min post injection in the SmartCube<jats:sup>\u00ae<\/jats:sup> test (5 and 10\u00a0mg\/kg, i.p.; about 45\u2010min session), decreased immobility in the forced swim test (1\u20133\u00a0mg\/kg, i.p.; 1\u201310\u00a0mg\/kg, p.o.; 30\u00a0min pretreatment, 6\u2010min trial), and decreased latency to approach food in the novelty\u2010suppressed feeding test after 29\u00a0days chronic administration once daily (5\u00a0mg\/kg but not 10\u00a0mg\/kg, p.o.; 15\u2010min trial). In addition, LF\u20103\u201088 exhibited a favorable profile in pharmacokinetic\/ADME\u2010Tox (absorption, distribution, metabolism, excretion, and toxicity) assays. This compound was also shown to cause no mortality in wild\u2010type Balb\/CJ mice when tested at 300\u00a0mg\/kg. These results further support the potential of potent and selective nicotinic partial agonists for use in the treatment of depression.<\/jats:p>","DOI":"10.1002\/prp2.26","type":"journal-article","created":{"date-parts":[[2014,3,14]],"date-time":"2014-03-14T01:59:55Z","timestamp":1394762395000},"source":"Crossref","is-referenced-by-count":3,"title":["The potent and selective <i>\u03b1<\/i>4<i>\u03b2<\/i>2*\/<i>\u03b1<\/i>6*\u2010nicotinic acetylcholine receptor partial agonist 2\u2010[5\u2010[5\u2010((<i>S<\/i>)Azetidin\u20102\u2010ylmethoxy)\u20103\u2010pyridinyl]\u20103\u2010isoxazolyl]ethanol demonstrates antidepressive\u2010like behavior in animal models and a favorable ADME\u2010tox profile"],"prefix":"10.1002","volume":"2","author":[{"given":"Li\u2010Fang","family":"Yu","sequence":"first","affiliation":[{"name":"Department of Medicinal Chemistry and Pharmacognosy University of Illinois at Chicago 833 South Wood Street Chicago Illinois 60612"},{"name":"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"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"J.","family":"Brek Eaton","sequence":"additional","affiliation":[{"name":"Division of Neurobiology Barrow Neurological Institute 350 West Thomas Road Phoenix Arizona 85013"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Han\u2010Kun","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Medicinal Chemistry and Pharmacognosy University of Illinois at Chicago 833 South Wood Street Chicago Illinois 60612"},{"name":"Institute of Biomedical Sciences and School of Life Sciences East China Normal University 500 Dongchuan Road Shanghai 200241 China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Emily","family":"Sabath","sequence":"additional","affiliation":[{"name":"PsychoGenics, Inc. 765 Old Saw 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