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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.

journal_name

Bioorg Med Chem

journal_title

Bioorganic & medicinal chemistry

authors

Fuchs A,Baur R,Schoeder C,Sigel E,Müller CE

doi

10.1016/j.bmc.2014.10.027

subject

Has Abstract

pub_date

2014-12-15 00:00:00

pages

6908-17

issue

24

eissn

0968-0896

issn

1464-3391

pii

S0968-0896(14)00748-2

journal_volume

22

pub_type

杂志文章

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