Retrochalcone

21133889

Background and purpose: Flavonoids, important plant pigments, have been shown to allosterically modulate brain GABA(A) receptors (GABA(A)Rs). We previously reported that trans-6,4′-dimethoxyretrochalcone (Rc-OMe), a hydrolytic derivative of the corresponding flavylium salt, displayed nanomolar affinity for the benzodiazepine binding site of GABA(A)Rs. Here, we evaluate the functional modulations of Rc-OMe, along with two other synthetic derivatives trans-6-bromo-4′-methoxyretrochalcone (Rc-Br) and 4,3′-dimethoxychalcone (Ch-OMe) on GABA(A)Rs.
Experimental approach: Whole-cell patch-clamp recordings were made to determine the effects of these derivatives on GABA(A)Rs expressed in HEK-293 cells and in hippocampal CA1 pyramidal and thalamic neurones from rat brain.
Key results: Rc-OMe strongly potentiated GABA-evoked currents at recombinant α(1-4)β(2)γ(2s) and α(4)β(3)δ receptors but much less at α(1)β(2) and α(4)β(3). Rc-Br and Ch-OMe potentiated GABA-evoked currents at α(1)β(2)γ(2s). The potentiation by Rc-OMe was only reduced at α(1)H101Rβ(2)γ(2s) and α(1)β(2)N265Sγ(2s), mutations known to abolish the potentiation by diazepam and loreclezole respectively. The modulation of Rc-OMe and pentobarbital as well as by Rc-OMe and the neurosteroid 3α,21-dihydroxy-5α-pregnan-20-one was supra-additive. Rc-OMe modulation exhibited no apparent voltage-dependence, but was markedly dependent on GABA concentration. In neurones, Rc-Br slowed the decay of spontaneous inhibitory postsynaptic currents and both Rc-OMe and Rc-Br positively modulated synaptic and extrasynaptic diazepam-insensitive GABA(A)Rs.
Conclusions and implications: The trans-retrochalcones are powerful positive allosteric modulators of synaptic and extrasynaptic GABA(A)Rs. These novel modulators act through an original mode, thus making them putative drug candidates in the treatment of GABA(A)-related disorders in vivo.
© 2011 The Authors. British Journal of Pharmacology © 2011 The British Pharmacological Society.

Echinatin; Esophageal squamous cell carcinoma; Reactive oxygen species; c-Jun N-terminal kinase; p38.

Retrochalcone Derivatives Are Positive Allosteric Modulators at Synaptic and Extrasynaptic GABA(A) Receptors in Vitro

Ruotian Jiang 1 , Akiko Miyamoto, Adeline Martz, Alexandre Specht, Hitoshi Ishibashi, Marie Kueny-Stotz, Stefan Chassaing, Raymond Brouillard, Lia Prado de Carvalho, Maurice Goeldner, Junichi Nabekura, Mogens Nielsen, Thomas Grutter

2011 Mar

24248440

Three O-methyltransferases which catalyze S-adenosyl-L-methionine (SAM)-dependent O-methylation of licodione (LMT), flavone/flavonol (FMT), and caffeic acid (CMT) were separated from the callus culture of Glycyrrhiza echinata, and characteristic differences between their pH optima and Mg(2+) requirement for activity were demonstrated. The activity of LMT, which is involved in retrochalcone (echinatin) biosynthesis, but not of FMT or CMT, was found to be stimulated when suspension-cultured G. echinata cells were treated with yeast extract (YE), which causes rapid production of echinatin in the cells. Cycloheximide suppressed both the YE-induced echinatin formation and LMT enhancement. The results indicate a selective induction of retrochalcone pathway in Glycyrrhiza cells in response to stress.

Regulation of Retrochalcone Biosynthesis: Activity Changes of O-methyltransferases in the Yeast Extract-Induced Glycyrrhiza Echinata Cells

S Ayabe 1 , A Udagawa, K Iida, T Yoshikawa, T Furuya

1987 Feb