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


METHODS
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.


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
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.
Laboratoire de Biophysicochimie des Récepteurs Canaux, UMR 7199 CNRS, Conception et Application de Molécules Bioactives, Faculté de Pharmacie, Université de Strasbourg, Illkirch, France.
Ruotian
R
Jiang
Akiko
A
Miyamoto
Adeline
A
Martz
Alexandre
A
Specht
Hitoshi
H
Ishibashi
Marie
M
Kueny-Stotz
Stefan
S
Chassaing
Raymond
R
Brouillard
Lia Prado
LP
de Carvalho
Maurice
M
Goeldner
Junichi
J
Nabekura
Mogens
M
Nielsen
Thomas
T
Grutter
D000818:Animals; D001569:Benzodiazepines / Q000378:metabolism; D056547:CA1 Region, Hippocampal / Q000187:drug effects*; D047188:Chalcones / Q000138:chemical synthesis / Q000494:pharmacology*; D057809:HEK293 Cells; D006801:Humans; D018377:Neurotransmitter Agents / Q000378:metabolism / Q000494:pharmacology; D018408:Patch-Clamp Techniques; D010957:Plasmids; D017966:Pyramidal Cells / Q000187:drug effects*; D051381:Rats; D017208:Rats, Wistar; D011963:Receptors, GABA-A / Q000378:metabolism*; D013237:Stereoisomerism; D020651:Ventral Thalamic Nuclei / Q000187:drug effects*; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
D047188:Chalcones; D018377:Neurotransmitter Agents; D011963:Receptors, GABA-A; D001569:Benzodiazepines; D005680:gamma-Aminobutyric Acid