GABA A Receptor Subtype-Selectivity of Novel Bicuculline Derivatives
2015
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 [ 3 H]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.
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