Retrochalcone derivatives are positive allosteric modulators at synaptic and extrasynaptic GABAA receptors in vitro

BACKGROUND AND PURPOSE Flavonoids, important plant pigments, have been shown to allosterically modulate brain GABAA receptors (GABAARs). 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 GABAARs. 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 GABAARs. EXPERIMENTAL APPROACH Whole‐cell patch‐clamp recordings were made to determine the effects of these derivatives on GABAARs 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 α1–4β2γ2s and α4β3δ receptors but much less at α1β2 and α4β3. Rc‐Br and Ch‐OMe potentiated GABA‐evoked currents at α1β2γ2s. The potentiation by Rc‐OMe was only reduced at α1H101Rβ2γ2s and α1β2N265Sγ2s, 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 GABAARs. CONCLUSIONS AND IMPLICATIONS The trans‐retrochalcones are powerful positive allosteric modulators of synaptic and extrasynaptic GABAARs. These novel modulators act through an original mode, thus making them putative drug candidates in the treatment of GABAA‐related disorders in vivo.