title: Nitrogenated honokiol derivatives allosterically modulate GABAA receptors and act as strong partial agonists.
abstract: 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 neolignan honokiol together with its isomer magnolol are the main constituents of Magnolia bark extracts. We have previously identified a nitrogen-containing honokiol derivative (3-acetylamino-4'-O-methylhonokiol, AMH) as a high efficient modulator of GABAA receptors. Here we further elucidate the structure-activity relation of a series of nitrogenated biphenyl-neolignan derivatives by analysing allosteric modulation and agonistic effects on α1β2γ2S GABAA receptors. The strongest IGABA enhancement was induced by compound 5 (3-acetamido-4'-ethoxy-3',5-dipropylbiphenyl-2-ol, Emax: 123.4±9.4% of IGABA-max) and 6 (5'-amino-2-ethoxy-3',5-dipropylbiphenyl-4'-ol, Emax: 117.7±13.5% of IGABA-max). Compound 5 displayed, however, a significantly higher potency (EC50=1.8±1.1 μM) than compound 6 (EC50=20.4±4.3 μM). Honokiol, AMH and four of the derivatives induced significant inward currents in the absence of GABA. Strong partial agonists were honokiol (inducing 78±6% of IGABA-max), AMH (63±6%), 5'-amino-2-O-methylhonokiol (1) (59±1%) and 2-methoxy-5'-nitro-3',5-dipropylbiphenyl-4'-ol (3) (52±1%). 3-N-Acetylamino-4'-ethoxy-3',5-dipropyl-biphenyl-4'-ol (5) and 3-amino-4'-ethoxy-3',5-dipropyl-biphenyl-4'-ol (7) were less efficacious but even more potent (5: EC50=6.9±1.0 μM; 7: EC50=33.2±5.1 μM) than the full agonist GABA.
authors.affiliation: Institute of Pharmaceutical Sciences, Pharmaceutical Chemistry, University of Graz, Schubertstrasse 1, 8010 Graz, Austria.
authors.forename: Marketa
authors.initials: M
authors.lastname: Bernaskova
authors.affiliation: Department of Pharmacology and Toxicology, University of Vienna, Althanstrasse 14, 1090 Vienna, Austria.
authors.forename: Angela
authors.initials: A
authors.lastname: Schoeffmann
authors.affiliation: Institute of Pharmaceutical Sciences, Pharmacognosy, University of Graz, Universitätsplatz 4, 8010 Graz, Austria; Institute of Zoology, University of Graz, Universitätsplatz 2, 8010 Graz, Austria. Electronic address: wolfgang.schuehly@uni-graz.at.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Schuehly
authors.affiliation: Institute of Pharmaceutical Sciences, Pharmaceutical Chemistry, University of Graz, Schubertstrasse 1, 8010 Graz, Austria.
authors.forename: Antje
authors.initials: A
authors.lastname: Hufner
authors.affiliation: Department of Pharmacology and Toxicology, University of Vienna, Althanstrasse 14, 1090 Vienna, Austria.
authors.forename: Igor
authors.initials: I
authors.lastname: Baburin
authors.affiliation: Department of Pharmacology and Toxicology, University of Vienna, Althanstrasse 14, 1090 Vienna, Austria.
authors.forename: Steffen
authors.initials: S
authors.lastname: Hering
mesh_terms: D000494:Allosteric Regulation / Q000187:drug effects*; D000818:Animals; D001713:Biphenyl Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D054333:Drug Partial Agonism; D005260:Female; D058785:GABA-A Receptor Agonists / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D017705:Lignans / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D031566:Magnolia / Q000737:chemistry; D015394:Molecular Structure; D009584:Nitrogen / Q000737:chemistry*; D009865:Oocytes / Q000187:drug effects / Q000378:metabolism; D011963:Receptors, GABA-A / Q000378:metabolism*; D013329:Structure-Activity Relationship; D014982:Xenopus laevis; D000498:Allyl Compounds; D010636:Phenols
chemical_list: D001713:Biphenyl Compounds; D058785:GABA-A Receptor Agonists; D017705:Lignans; D009584:Nitrogen; D011963:Receptors, GABA-A; C005499:honokiol; D000498:Allyl Compounds; D010636:Phenols
keywords: GABA(A) receptor; Honokiol derivatives; Magnolia; Nitrogenation