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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 ?1?2?2 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 3?M, 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 ?1?2?2 and the ?1?1?2 subtypes compared to honokiol, and thus improved subtype selectivity.

SUBMITTER: Rycek L

PROVIDER: S-EPMC4297288 | biostudies-literature | 2015 Jan

REPOSITORIES: biostudies-literature

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Metal-assisted synthesis of unsymmetrical magnolol and honokiol analogs and their biological assessment as GABAA receptor ligands.

Rycek Lukas L Puthenkalam Roshan R Schnürch Michael M Ernst Margot M Mihovilovic Marko D MD

Bioorganic & medicinal chemistry letters 20141104 2

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 th ...[more]

PMID: 25510374

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