MRK-016

MRK-016 is a functionally selective inverse agonist of α₅ subunit-containing GABA_A receptors.¹ It selectively binds to α₁-, α₂-, α₃-, and α₅ subunit-containing GABA_A receptors (K_is = 0.83, 0.85, 0.77, and 1.4 nM, respectively) over those containing α₄ or α₆ subunits (K_is = 395 and >4,000 nM, respectively). It also selectively inhibits GABA-induced currents in mouse fibroblast L-M(TK-) cells expressing α₅ subunit-containing GABA_A receptors over those containing α₁, α₂, or α₃ subunits. MRK-016 (3 mg/kg) reverses LPS-induced decreases in Bdnf expression, but not LPS-induced increases in amyloid-β levels, in the mouse hippocampus.² It reverses LPS-induced inhibition of contextual fear acquisition in the same study, indicating a reversal of memory consolidation deficits.² It enhances the performance of wild-type rats in a delayed matching-to-place water maze when administered at doses of 0.3, 1, and 3 mg/kg, indicating nootropic properties.¹ MRK-016 also reduces immobility in the forced swim test in mice, an effect that can be blocked by the AMPA glutamate receptor antagonist NBQX (Item No. 14914).³ It does not potentiate proconvulsant activity induced by pentylenetetrazole (Item No. 18682) in mice when administered at doses up to 10 mg/kg.¹

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1. Chambers, M.S., Atack, J.R., Carling, R.W., et al. An orally bioavailable, functionally selective inverse agonist at the benzodiazepine site of GABA_A α5 receptors with cognition enhancing properties. J. Med. Chem. 47(24), 5829-5832 (2004).

2. Eimerbrink, M.J., Pendry, R.J., Hodges, S.L., et al. The α5-GABAAR inverse agonist MRK-016 upregulates hippocampal BDNF expression and prevents cognitive deficits in LPS-treated mice, despite elevations in hippocampal Aβ. Behav. Brain Res. 359, 871-877 (2019).

3. Zanos, P., Nelson, M.E., Highland, J.N., et al. A negative allosteric modulator for α5 subunit-containing GABA receptors exerts a rapid and persistent antidepressant-like action without the side effects of the nmda receptor antagonist ketamine in mice. eNeuro 4(1), e0285-0216.2017 (2017).