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Metal-assisted synthesis of unsymmetrical magnolol and honokiol analogs and their biological assessment as GABAA receptor ligands.
- Source :
-
Bioorganic & medicinal chemistry letters [Bioorg Med Chem Lett] 2015 Jan 15; Vol. 25 (2), pp. 400-3. Date of Electronic Publication: 2014 Nov 04. - Publication Year :
- 2015
-
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.<br /> (Copyright © 2014 The Authors. Published by Elsevier Ltd.. All rights reserved.)
- Subjects :
- Animals
Anti-Inflammatory Agents, Non-Steroidal chemistry
Anti-Inflammatory Agents, Non-Steroidal pharmacology
Biphenyl Compounds pharmacology
Lignans pharmacology
Molecular Structure
Oocytes cytology
Oocytes metabolism
Patch-Clamp Techniques
Protein Subunits
Rats
Recombinant Proteins metabolism
Structure-Activity Relationship
Xenopus growth & development
Xenopus metabolism
Biphenyl Compounds chemistry
GABA Modulators chemistry
GABA Modulators metabolism
Lignans chemistry
Metals pharmacology
Oocytes drug effects
Receptors, GABA-A metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1464-3405
- Volume :
- 25
- Issue :
- 2
- Database :
- MEDLINE
- Journal :
- Bioorganic & medicinal chemistry letters
- Publication Type :
- Academic Journal
- Accession number :
- 25510374
- Full Text :
- https://doi.org/10.1016/j.bmcl.2014.10.091