Use of bicuculline, a GABA antagonist, as a template for the development of a new class of ligands showing positive allosteric modulation of the GABA(A) receptor.
Analogues of bicuculline devoid of the benzo ring fused to the lactone moiety were prepared by reacting 2-(tert-butyl-dimethylsiloxy)furans with 3,4-dihydroisoquinolinium salts. Some of these compounds (e.g., ROD185, 8) acted as modulators of the GABAA receptor, displacing ligands of the benzodiazepine binding site. They also strongly stimulated GABA currents mediated by recombinant GABA(A) receptors expressed in Xenopus oocytes.
Razet
R
R
Institut de Chimie des Substances Naturelles, Centre National de la Recherche Scientifique, Gif-sur-Yvette, France.
Thomet
U
U
Furtmüller
R
R
Jursky
F
F
Sigel
E
E
Sieghart
W
W
Dodd
R H
RH
D000494:Allosteric Regulation; D001640:Bicuculline / Q000494:pharmacology*; D018756:GABA Antagonists / Q000494:pharmacology*; D008024:Ligands; D011963:Receptors, GABA-A / Q000187:drug effects* / Q000378:metabolism
D018756:GABA Antagonists; D008024:Ligands; D011963:Receptors, GABA-A; D001640:Bicuculline