RO5126946

RO5126946 is a selective, orally active α7 nAChR allosteric potentiator with EC₅₀ values of 0.06 μM (hα7 nAChR) and 770 nM (α7 nAChR), and it crosses the blood-brain barrier. RO5126946 enhances synaptic transmission and positively modulates GABA-ergic responses by increasing peak current, slowing current decay, and elevating the frequency of spontaneous inhibitory postsynaptic currents, without affecting the recovery of receptors from the desensitized state. RO5126946 not only enhances subthreshold nicotine effects and improves associative learning, but also does not interfere with the original pro-cognitive effects of nicotine. RO5126946 can be used to study cognitive impairments associated with diseases such as Alzheimer's disease and schizophrenia^[1]. In Vitro:RO5126946 (0.01-3 μM) potently potentiates nicotine-evoked currents in cultured rat hippocampal neurons via an α₇ nAChR-dependent mechanism, with an EC₅₀ of 7.7 ± 2.0 × 10^-7 M and maximum potentiation of 2800% ± 730%, and this effect is independent of glutamate or GABAₐ receptor activity^[1].
RO5126946 (0.3-1 μM) does not reactivate fully desensitized α₇ nAChRs in cultured rat hippocampal neurons^[1].
RO5126946 (0.3 μM; ~5 min) potentiates nicotine-induced increases in spontaneous inhibitory postsynaptic current frequency in cultured rat hippocampal neurons, an effect dependent on action potential propagation^[1]. In Vivo:RO5126946 (3-30 mg/kg; p.o.; single dose 60 minutes before training) reverses scopolamine-induced associative memory deficits in rats, with 10 and 30 mg/kg fully restoring freezing behavior to vehicle levels^[1].
RO5126946 (1 mg/kg; p.o.; single dose 60 minutes before training) potentiates the procognitive effects of a subthreshold dose of nicotine to reverse scopolamine-induced associative memory deficits in rats^[1].
RO5126946 (3 mg/kg; p.o.; single dose 60 minutes before training) reverses scopolamine-induced associative memory deficits in rats and does not interfere with the procognitive effects of an effective dose of nicotine^[1].