title: Metal-assisted synthesis of unsymmetrical magnolol and honokiol analogs and their biological assessment as GABAA receptor ligands.
abstract: We present the synthesis of new derivatives of natural products magnolol (1) and honokiol (2) and their evaluation as allosteric ligands for modulation of GABAA receptor activity. New derivatives were prepared via metal assisted cross-coupling reactions in two consecutive steps. Compounds were tested by means of two-electrode voltage clamp electrophysiology at the α1β2γ2 receptor subtype at low GABA concentrations. We have identified several compounds enhancing GABA induced current (IGABA) in the range similar or even higher than the lead structures. At 3μM, compound 8g enhanced IGABA by factor of 443, compared to 162 and 338 of honokiol and magnolol, respectively. Furthermore, 8g at EC10-20 features a much bigger window of separation between the α1β2γ2 and the α1β1γ2 subtypes compared to honokiol, and thus improved subtype selectivity.
authors.affiliation: Vienna University of Technology, Institute of Applied Synthetic Chemistry, Getreidemarkt 9/163-OC, 1060 Vienna, Austria.
authors.forename: Lukas
authors.initials: L
authors.lastname: Rycek
authors.affiliation: Medical University of Vienna, Department of Molecular Neurosciences, Spitalgasse 4, 1090 Vienna, Austria.
authors.forename: Roshan
authors.initials: R
authors.lastname: Puthenkalam
authors.affiliation: Vienna University of Technology, Institute of Applied Synthetic Chemistry, Getreidemarkt 9/163-OC, 1060 Vienna, Austria.
authors.forename: Michael
authors.initials: M
authors.lastname: Schnürch
authors.affiliation: Medical University of Vienna, Department of Molecular Neurosciences, Spitalgasse 4, 1090 Vienna, Austria.
authors.forename: Margot
authors.initials: M
authors.lastname: Ernst
authors.affiliation: Vienna University of Technology, Institute of Applied Synthetic Chemistry, Getreidemarkt 9/163-OC, 1060 Vienna, Austria. Electronic address: mmihovil@poptuwien.ac.at.
authors.forename: Marko D
authors.initials: MD
authors.lastname: Mihovilovic
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000737:chemistry / Q000494:pharmacology; D001713:Biphenyl Compounds / Q000737:chemistry* / Q000494:pharmacology; D018757:GABA Modulators / Q000737:chemistry* / Q000378:metabolism*; D017705:Lignans / Q000737:chemistry* / Q000494:pharmacology; D008670:Metals / Q000494:pharmacology*; D015394:Molecular Structure; D009865:Oocytes / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D018408:Patch-Clamp Techniques; D021122:Protein Subunits; D051381:Rats; D011963:Receptors, GABA-A / Q000378:metabolism*; D011994:Recombinant Proteins / Q000378:metabolism; D013329:Structure-Activity Relationship; D014981:Xenopus / Q000254:growth & development / Q000378:metabolism; D000498:Allyl Compounds; D010636:Phenols
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D001713:Biphenyl Compounds; D018757:GABA Modulators; D017705:Lignans; D008670:Metals; D021122:Protein Subunits; D011963:Receptors, GABA-A; D011994:Recombinant Proteins; C005498:magnolol; C005499:honokiol; D000498:Allyl Compounds; D010636:Phenols
keywords: Cross-coupling; GABA(A); Honokiol; Magnolol; Subtype selectivity