posted on 2024-02-22, 18:34authored byAllison
L. Germann, Yuanjian Xu, Douglas F. Covey, Alex S. Evers, Gustav Akk
Activation of the GABAA receptor is associated
with
numerous behavioral end points ranging from anxiolysis to deep anesthesia.
The specific behavioral effect of a GABAergic compound is considered
to correlate with the degree of its functional effect on the receptor.
Here, we tested the hypothesis that a low-efficacy allosteric potentiator
of the GABAA receptor may act, due to a ceiling effect,
as a sedative with reduced and limited action. We synthesized a derivative,
named (3α,5β)-20-methyl-pregnane-3,20-diol (KK-235), of
the GABAergic neurosteroid 5β-pregnane-3α,20α-diol.
Using electrophysiology, we showed that KK-235 is a low-efficacy potentiator
of the synaptic-type α1β2γ2L GABAA receptor.
In the zebrafish larvae behavioral assay, KK-235 was found to only
partially block the inverted photomotor response (PMR) and to weakly
reduce swimming behavior, whereas the high-efficacy GABAergic steroid
(3α,5α,17β)-3-hydroxyandrostane-17-carbonitrile
(ACN) fully blocked PMR and spontaneous swimming. Coapplication of
KK-235 reduced the potentiating effect of ACN in an electrophysiological
assay and dampened its sedative effect in behavioral experiments.
We propose that low-efficacy GABAergic potentiators may be useful
as sedatives with limited action.