{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,12]],"date-time":"2025-10-12T04:04:03Z","timestamp":1760241843982,"version":"build-2065373602"},"reference-count":26,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2018,10,4]],"date-time":"2018-10-04T00:00:00Z","timestamp":1538611200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100002428","name":"Austrian Science Fund","doi-asserted-by":"publisher","award":["P21241"],"award-info":[{"award-number":["P21241"]}],"id":[{"id":"10.13039\/501100002428","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>In traditional Asian medicinal systems, preparations of the root and stem bark of Magnolia species are widely used to treat anxiety and other nervous disturbances. The biphenyl-type neolignans honokiol and magnolol are the main constituents of Magnolia bark extracts. In the central nervous system, Magnolia bark preparations that contain honokiol are thought to primarily interact with \u03b3-aminobutyric acid A (GABAA) receptors. However, stress responses inherently involve the noradrenergic system, which has not been investigated in the pharmacological mechanism of honokiol. We present here interactions of honokiol and other synthesized biphenyl-type neolignans and diphenylmethane analogs with the norepinephrine transporter (NET), which is responsible for the synaptic clearance of norepinephrine and the target of many anxiolytics. Of the synthesized compounds, 16 are new chemical entities, which are fully characterized. The 52 compounds tested show mild, non-potent interactions with NET (IC50 &gt; 100 \u00b5M). It is thus likely that the observed anxiolytic effects of, e.g., Magnolia preparations, are not due to direct interaction with the noradrenergic system.<\/jats:p>","DOI":"10.3390\/molecules23102536","type":"journal-article","created":{"date-parts":[[2018,10,5]],"date-time":"2018-10-05T12:16:44Z","timestamp":1538741804000},"page":"2536","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Bioinspired Honokiol Analogs and Their Evaluation for Activity on the Norepinephrine Transporter"],"prefix":"10.3390","volume":"23","author":[{"given":"Kristen","family":"Stout","sequence":"first","affiliation":[{"name":"Rollins School of Public Health, Emory University, 1518 Clifton Road, NE, Claudia Nance Rollins Bldg, Atlanta, GA 30322, USA"},{"name":"Columbia University Mailman School of Public Health, 722 West 168th Street, Room 1411B, New York, NY 10032, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marketa","family":"Bernaskova","sequence":"additional","affiliation":[{"name":"Institute of Pharmaceutical Sciences, Pharmaceutical Chemistry, Universit\u00e4tsplatz 1, University of Graz, 8010 Graz, Austria"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8984-1284","authenticated-orcid":false,"given":"Gary W.","family":"Miller","sequence":"additional","affiliation":[{"name":"Rollins School of Public Health, Emory University, 1518 Clifton Road, NE, Claudia Nance Rollins Bldg, Atlanta, GA 30322, USA"},{"name":"Columbia University Mailman School of Public Health, 722 West 168th Street, Room 1411B, New York, NY 10032, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7618-5636","authenticated-orcid":false,"given":"Antje","family":"Hufner","sequence":"additional","affiliation":[{"name":"Institute of Pharmaceutical Sciences, Pharmaceutical Chemistry, Universit\u00e4tsplatz 1, University of Graz, 8010 Graz, Austria"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wolfgang","family":"Schuehly","sequence":"additional","affiliation":[{"name":"Institute of Pharmaceutical Sciences, Pharmacognosy, Universit\u00e4tsplatz 4, University of Graz, 8010 Graz, Austria"},{"name":"Institute of Biology, Universit\u00e4tsplatz 2, University of Graz, 8010 Graz, Austria"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2018,10,4]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"307","DOI":"10.1016\/j.jep.2015.05.045","article-title":"Prescription patterns of Chinese herbal products for patients with sleep disorder and major depressive disorder in Taiwan","volume":"171","author":"Chen","year":"2015","journal-title":"J. Ethnopharm."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"135","DOI":"10.1021\/np9702446","article-title":"Identification of magnolol and honokiol as anxiolytic agents in extracts of saiboku-to, an oriental herbal medicine","volume":"61","author":"Maruyama","year":"1998","journal-title":"J. Nat. Prod."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1111\/j.1527-3458.2000.tb00136.x","article-title":"Overview of the pharmacological features of honokiol","volume":"6","author":"Maruyama","year":"2000","journal-title":"CNS Drug Rev."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"34","DOI":"10.1159\/000056110","article-title":"Honokiol and Magnolol Selectively Interact with GABAA Receptor Subtypes in vitro","volume":"63","author":"Ai","year":"2001","journal-title":"Pharmacology"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"313","DOI":"10.1016\/S0006-3223(03)00676-0","article-title":"Regulation of the norepinephrine transporter by chronic administration of antidepressants","volume":"55","author":"Benmansour","year":"2004","journal-title":"Biol. Psychiatry"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1186\/alzrt175","article-title":"Targeting norepinephrine in mild cognitive impairment and Alzheimer\u2019s disease","volume":"5","author":"Chalermpalanupap","year":"2013","journal-title":"Alzheimers Res. Ther."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"801","DOI":"10.1016\/j.bcp.2009.10.004","article-title":"Good night and good luck: Norepinephrine in sleep pharmacology","volume":"79","author":"Mitchell","year":"2010","journal-title":"Biochem. Pharm."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"65","DOI":"10.2174\/092986706775197999","article-title":"Privileged structures as leads in medicinal chemistry","volume":"13","author":"Costantino","year":"2006","journal-title":"Curr. Med. Chem."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"4459","DOI":"10.1016\/j.bmc.2009.05.018","article-title":"Design and synthesis of ten biphenyl-neolignan derivatives and their in vitro inhibitory potency against cyclooxygenase-1\/2 activity and 5-lipoxygenase-mediated LTB4-formation","volume":"17","author":"Prettner","year":"2009","journal-title":"Bioorg. Med. Chem."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"5349","DOI":"10.1021\/jm200186n","article-title":"Modulation of GABAA-Receptors by Honokiol and Derivatives: Subtype Selectivity and Structure Activity Relationship","volume":"54","author":"Taferner","year":"2011","journal-title":"J. Med. Chem."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"6757","DOI":"10.1016\/j.bmc.2015.08.034","article-title":"Nitrogenated honokiol derivatives allosterically modulate GABAA receptors and act as strong partial agonists","volume":"23","author":"Bernaskova","year":"2015","journal-title":"Bioorg. Med. Chem."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1053","DOI":"10.1016\/j.chembiol.2011.05.012","article-title":"Mechanisms of Osteoclastogenesis Inhibition by a Novel Class of Biphenyl-Type Cannabinoid CB2 Receptor Inverse Agonists","volume":"18","author":"Schuehly","year":"2011","journal-title":"Chem. Biol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1223","DOI":"10.3390\/molecules19011223","article-title":"Synthesis of Tetrahydrohonokiol Derivates and Their Evaluation for Cytotoxic Activity against CCRF-CEM Leukemia, U251 Glioblastoma and HCT-116 Colon Cancer Cells","volume":"19","author":"Bernaskova","year":"2014","journal-title":"Molecules"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1378","DOI":"10.1021\/jm01241a034","article-title":"Some 2-Substituted 2H-l,4-Benzoxazin-3(4H)-ones","volume":"5","author":"Wheeler","year":"1962","journal-title":"J. Med. Chem."},{"key":"ref_15","first-page":"177","article-title":"Sur l\u2019action de l\u2019\u00e9ther chloxycarbonique sur l\u2019ammidophenol","volume":"25","author":"Groenvik","year":"1876","journal-title":"Bull. Soc. Chim. Fr."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"227","DOI":"10.1023\/A:1024177708613","article-title":"Synthesis of Fmoc-amino acid chlorides assisted by ultrasonication, a rapid approach","volume":"9","author":"Kantharaju","year":"2002","journal-title":"Lett. Pept. Sci."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"9769","DOI":"10.1016\/S0040-4039(98)02169-8","article-title":"Synthesis of peptides employing Fmoc-amino acid chlorides and commercial zinc dust","volume":"39","author":"Gopi","year":"1998","journal-title":"Tetrahedron Lett."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"4475","DOI":"10.1021\/ja010221k","article-title":"Enantiospecific Synthesis of the Proposed Structure of the Antitubercular Marine Diterpenoid Pseudopteroxazole: Revision of Stereochemistry","volume":"123","author":"Johnson","year":"2001","journal-title":"J. Am. Chem. Soc."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1319","DOI":"10.1021\/jm034248l","article-title":"Evaluation of potent and selective small-molecule antagonists for the CXCR2 chemokine receptor","volume":"47","author":"Widdowson","year":"2004","journal-title":"J. Med. Chem."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"3012","DOI":"10.1021\/jo981110f","article-title":"The Reactivity of o-Hydroxybenzyl Alcohol and Derivatives in Solution at Elevated Temperatures","volume":"64","author":"Dorrestijn","year":"1999","journal-title":"J. Org. Chem."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"2211","DOI":"10.1055\/s-2006-950398","article-title":"Sequential double Claisen rearrangement and two-directional ring-closing metathesis as a route to various benzofused bisoxepin and bisoxocin derivatives","volume":"14","author":"Chattopadhyay","year":"2006","journal-title":"Synlett"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"252","DOI":"10.1016\/j.ejmech.2016.03.072","article-title":"Synthesis and pharmacological evaluation of new biphenylic derivatives as CB2 receptor ligands","volume":"116","author":"Bertini","year":"2016","journal-title":"Eur. J. Med. Chem."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"168","DOI":"10.1016\/j.jneumeth.2007.12.004","article-title":"Validation of a fluorescence-based high throughput assay for the measurement of neurotransmitter transporter uptake activity","volume":"169","author":"Nielsen","year":"2008","journal-title":"J. Neurosci. Methods"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"357","DOI":"10.1016\/j.jneumeth.2012.06.002","article-title":"A fluorescent-based assay for live cell, spatially resolved assessment of vesicular monoamine transporter 2-mediated neurotransmitter transport","volume":"209","author":"Bernstein","year":"2012","journal-title":"J. Neurosci. Methods"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"274","DOI":"10.1046\/j.1471-4159.1998.71010274.x","article-title":"Regulation of extracellular dopamine by the norepinephrine transporter","volume":"71","author":"Yamamoto","year":"1998","journal-title":"J. Neurochem."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1038\/nrn1008","article-title":"Plasma membrane monoamine transporters: Structure, regulation and function","volume":"4","author":"Torres","year":"2003","journal-title":"Nat. Rev. Neurosci."}],"container-title":["Molecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1420-3049\/23\/10\/2536\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T15:24:03Z","timestamp":1760196243000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1420-3049\/23\/10\/2536"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2018,10,4]]},"references-count":26,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2018,10]]}},"alternative-id":["molecules23102536"],"URL":"https:\/\/doi.org\/10.3390\/molecules23102536","relation":{},"ISSN":["1420-3049"],"issn-type":[{"type":"electronic","value":"1420-3049"}],"subject":[],"published":{"date-parts":[[2018,10,4]]}}}