GABA_A Receptor Subtype-Selectivity of Novel Bicuculline Derivatives

Title:GABA_A Receptor Subtype-Selectivity of Novel Bicuculline Derivatives

Volume: 22 Issue: 6

Author(s): Joachim Ramerstorfer, Verena Foppa, Hanna Thiery, Philippe Hermange, Simon Janody, Michael L. Berger, Robert H. Dodd and Werner Sieghart

Affiliation:

Keywords: Benzodiazepine binding site, GABA_A receptor, novel binding site, novel ligands, positive modulators, ROD 185.

Abstract: GABA_A receptors are the major inhibitory neurotransmitter receptors in the central nervous system and are targets of clinically important drugs modulating GABA induced ion flux by interacting with distinct allosteric binding sites. ROD 185 is a previously investigated structural analogue of the GABA site antagonist bicuculline, and a positive allosteric modulator acting via the benzodiazepine binding site. Here, we investigated 13 newly synthesized structural analogues of ROD 185 for their interaction with rat GABA_A receptors. Using [³H]flunitrazepam binding assays, we identified four compounds exhibiting a higher affinity for the benzodiazepine binding site than ROD 185. Two electrode voltage clamp electrophysiology at recombinant GABA_A receptors indicated that most of these compounds positively modulated GABA-induced currents at these receptors. Additionally, these experiments revealed that this compound class not only interacts with the benzodiazepine binding site at αβγ receptors but also with a novel, so far unidentified binding site present in αβ receptors. Compounds with a high affinity for the benzodiazepine binding site stimulated GABA-induced currents stronger at αβγ than at αβ receptors and preferred α3β3γ2 receptors. Compounds showing equal or smaller effects at αβγ compared to αβ receptors differentially interacted with various αβ or αβγ receptor subtypes. Surprisingly, five of these compounds interacting with αβ receptors showed a strong stimulation at α6β3γ2 receptors. The absence of any direct effects at GABA_A receptors, as well as their potential selectivity for receptor subtypes not being addressed by benzodiazepines, make this compound class to a starting point for the development of drugs with a possible clinical importance.

Cite this article as:

Ramerstorfer Joachim, Foppa Verena, Thiery Hanna, Hermange Philippe, Janody Simon, Berger L. Michael, Dodd H. Robert and Sieghart Werner, GABA_A Receptor Subtype-Selectivity of Novel Bicuculline Derivatives, Current Medicinal Chemistry 2015; 22 (6) . https://dx.doi.org/10.2174/0929867321666141106110356