Rycek L et al. (2015), Metal-assisted synthesis of unsymmetrical magno...

XB-ART-51319

Bioorg Med Chem Lett 2015 Jan 15;252:400-3. doi: 10.1016/j.bmcl.2014.10.091.

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

Rycek L , Puthenkalam R , Schnürch M , Ernst M , Mihovilovic MD .

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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.

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Species referenced: Xenopus
Genes referenced: gabarap

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	Graphical Abstract
	Figure 1. Dose–response curves for IGABA potentiation by 8g and honokiol in α1β1γ2 and α1β2γ2 using GABA EC10–20.
	Scheme 1. Structure of lead compounds and of new derivatives.
	Scheme 2. Introduction of allyl moiety.
	Scheme 3. Introduction of the aryl moiety.