Retrochalcone derivatives are positive allosteric modulators at synaptic and extrasynaptic GABA(A) receptors in vitro.

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)ß(2)γ(2s) and α(4)ß(3)δ receptors but much less at α(1)ß(2) and α(4)ß(3). Rc-Br and Ch-OMe potentiated GABA-evoked currents at α(1)ß(2)γ(2s). The potentiation by Rc-OMe was only reduced at α(1)H101Rß(2)γ(2s) and α(1)ß(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.

Flavylium salts as in vitro precursors of potent ligands to brain GABA-A receptors.

The synthesis of a series of derivatized flavylium cations was undertaken and the affinity to the benzodiazepine binding site of the GABA-A receptor evaluated. The observed high affinity for some derivatives (sub-muM range) was explained by an in vitro transformation of the flavylium cations into the corresponding trans-retrochalcones, components which are proposed to be the active species in this series.

Anti-mitotic properties of resveratrol analog (Z)-3,5,4'-trimethoxystilbene.

(Z)-3,5,4'-Trimethoxystilbene is a natural polyphenol present in five different plants, Virola cuspidata, Virola elongata, Centipeda minima, Schoenus nigricans and Rheum undulatum. This molecule was prepared in a three-step sequence in good overall yield. The isomerisation from the (E)- to (Z)-isomer is performed using UV irradiation. Biological investigations were conducted on a human colon cancer cell line (Caco-2) with anti-mitotic activities. Growth was completely arrested at an added 0.4 microM level of (Z)-3,5,4'-trimethoxystilbene. This agent is 100-fold more active than resveratrol or (E)-3,5,4'-trihydroxystilbene, and the mechanism of this process involves an inhibition of tubulin polymerisation in a dose dependent manner.

Croton lobatus, an African medicinal plant: spectroscopic and chemical elucidation of its many constituents.

The chemical constituents of the African medicinal plant Croton lobatus were elucidated and characterised using 1D and 2D-NMR analysis and the application of the technique of High Resolution Electron Ionization Mass Spectrometry (HREIMS) and High Resolution Mass Spectrometry (HRMS). The novel triglyceride lobaceride or 3-((6Z,9Z)dodeca-6,9-dienoyloxy)-2-octanoyloxypropyl (6Z,9Z)dodeca-6,9-dienoate, along with ten compounds were isolated from the stems and leaves of Croton lobatus.

Concise synthesis of dihydrochalcones via palladium-catalyzed coupling of aryl halides and 1-aryl-2-propen-1-ols.

An expedient route to substituted dihydrochalcones is reported. The key step is a palladium-assisted arylation of 1-aryl-2-propen-1-ols. This two-step/one-purification process allows the synthesis of a wide range of compounds with original substitution patterns, including polyphenolic derivatives.

Resveratrol analog (Z)-3,5,4'-trimethoxystilbene is a potent anti-mitotic drug inhibiting tubulin polymerization.

Resveratrol (3,5,4'-trihydroxystilbene) a natural polyphenol present in medicinal plants, grapes and wines, has potent chemopreventive properties on intestinal carcinogenesis. A methylated derivative (Z-3,5,4'-trimethoxystilbene: R3) was synthesized. R3 at 0.3 microM exerted a 80% growth inhibition of human colon cancer Caco-2 cells and arrested growth completely at 0.4 microM (R3 was 100-fold more active than resveratrol). The cis conformation of R3 was also 100-fold more potent than the trans isomer. R3 (0.3 microM) caused cell cycle arrest at the G2/M phase transition. The drug inhibited tubulin polymerization in a dose-dependent manner (IC50=4 microM), and it reduced also by 2-fold ornithine decarboxylase and s-adenosylmethionine decarboxylase activities. This caused the depletion of the polyamines, putrescine and spermidine, which are growth factors for cancer cells. R3 inhibited partially colchicine binding to its binding site on tubulin, indicating that R3 either partially overlaps with colchicine binding or that R3 binds to a specific site of tubulin that is not identical with the colchicine binding site modifying colchicine binding by allosteric influences. The resveratrol derivative (Z)-3,5,4'-trimethoxystilbene (R3) is an interesting anti-mitotic drug that exerts cytotoxic effects by depleting the intracellular pool of polyamines and by altering microtubule polymerization. Such a drug may be useful for the treatment of neoplastic diseases.