Back
Structural analogues of the natural products magnolol and honokiol as potent allosteric potentiators of GABA(A) receptors.
Journal article

Structural analogues of the natural products magnolol and honokiol as potent allosteric potentiators of GABA(A) receptors.

  • Fuchs A PharmaCenter Bonn, Pharmaceutical Institute, Pharmaceutical Chemistry I, University of Bonn, An der Immenburg 4, 53121 Bonn, Germany.
  • Baur R Institute of Biochemistry and Molecular Medicine, University of Bern, Bühlstrasse 28, 3012 Bern, Switzerland.
  • Schoeder C PharmaCenter Bonn, Pharmaceutical Institute, Pharmaceutical Chemistry I, University of Bonn, An der Immenburg 4, 53121 Bonn, Germany.
  • Sigel E Institute of Biochemistry and Molecular Medicine, University of Bern, Bühlstrasse 28, 3012 Bern, Switzerland.
  • Müller CE 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.
Show more…
  • 2014-12-03
Published in:
  • Bioorganic & medicinal chemistry. - 2014
Allosteric modulation
GABA(A) receptor
Honokiol
Ion channel
Magnolol
Medicinal plant
Natural product
Positive allosteric modulator (PAM)
Synthesis
Allosteric Regulation
Animals
Biological Products
Biphenyl Compounds
Lignans
Oocytes
Patch-Clamp Techniques
Protein Binding
Protein Isoforms
Receptors, GABA-A
Structure-Activity Relationship
Xenopus
English 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.
Language
  • English
Open access status
closed
Identifiers
Persistent URL
https://sonar.rero.ch/global/documents/183442
Statistics
Document views: 12 File downloads: