title: Structural analogues of the natural products magnolol and honokiol as potent allosteric potentiators of GABA(A) receptors.
abstract: Biphenylic compounds related to the natural products magnolol and 4'-O-methylhonokiol were synthesized, evaluated and optimized as positive allosteric modulators (PAMs) of GABA(A) receptors. The most efficacious compounds were the magnolol analog 5-ethyl-5'-hexylbiphenyl-2,2'-diol (45) and the honokiol analogs 4'-methoxy-5-propylbiphenyl-2-ol (61), 5-butyl-4'-methoxybiphenyl-2-ol (62) and 5-hexyl-4'-methoxybiphenyl-2-ol (64), which showed a most powerful potentiation of GABA-induced currents (up to 20-fold at a GABA concentration of 3μM). They were found not to interfere with the allosteric sites occupied by known allosteric modulators, such as benzodiazepines and N-arachidonoylglycerol. These new PAMs will be useful as pharmacological tools and may have therapeutic potential for mono-therapy, or in combination, for example, with GABA(A) receptor agonists.
authors.affiliation: PharmaCenter Bonn, Pharmaceutical Institute, Pharmaceutical Chemistry I, University of Bonn, An der Immenburg 4, 53121 Bonn, Germany.
authors.forename: Alexander
authors.initials: A
authors.lastname: Fuchs
authors.affiliation: Institute of Biochemistry and Molecular Medicine, University of Bern, Bühlstrasse 28, 3012 Bern, Switzerland.
authors.forename: Roland
authors.initials: R
authors.lastname: Baur
authors.affiliation: PharmaCenter Bonn, Pharmaceutical Institute, Pharmaceutical Chemistry I, University of Bonn, An der Immenburg 4, 53121 Bonn, Germany.
authors.forename: Clara
authors.initials: C
authors.lastname: Schoeder
authors.affiliation: Institute of Biochemistry and Molecular Medicine, University of Bern, Bühlstrasse 28, 3012 Bern, Switzerland.
authors.forename: Erwin
authors.initials: E
authors.lastname: Sigel
authors.affiliation: PharmaCenter Bonn, Pharmaceutical Institute, Pharmaceutical Chemistry I, University of Bonn, An der Immenburg 4, 53121 Bonn, Germany; Institute of Biochemistry and Molecular Medicine, University of Bern, Bühlstrasse 28, 3012 Bern, Switzerland. Electronic address: christa.mueller@uni-bonn.de.
authors.forename: Christa E
authors.initials: CE
authors.lastname: Müller
mesh_terms: D000494:Allosteric Regulation; D000818:Animals; D001688:Biological Products / Q000737:chemistry* / Q000378:metabolism; D001713:Biphenyl Compounds / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D017705:Lignans / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D009865:Oocytes / Q000378:metabolism; D018408:Patch-Clamp Techniques; D011485:Protein Binding; D020033:Protein Isoforms / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D011963:Receptors, GABA-A / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D013329:Structure-Activity Relationship; D014981:Xenopus / Q000254:growth & development; D000498:Allyl Compounds; D010636:Phenols
chemical_list: D001688:Biological Products; D001713:Biphenyl Compounds; D017705:Lignans; D020033:Protein Isoforms; D011963:Receptors, GABA-A; C005498:magnolol; C005499:honokiol; D000498:Allyl Compounds; D010636:Phenols
keywords: Allosteric modulation; GABA(A) receptor; Honokiol; Ion channel; Magnolol; Medicinal plant; Natural product; Positive allosteric modulator (PAM); Synthesis