氨基丁酸A型受体亚型选择性的新型荷包牡丹碱衍生物

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:

关键词: 苯二氮平结合位点，氨基丁酸A型受体，新颖的结合位点，新型配体，正向调节，ROD185

摘要: 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:

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