JNJ-10397049

JNJ-10397049 is a potent, selective, and bioavailable antagonist of the orexin-2 receptor (OX2R) (K_B = 4.5 nM for OX2R versus 1.1 µM for OX1R).^1,2,3 It has no significant affinity for over 50 other neurotransmitters or neuropeptide receptors.¹ Applied subcutaneously to rats, JNJ-10397049 decreases the latency to persistent sleep and increases persistent sleep time.¹ This compound produces a widespread attenuation of D-amphetamine-induced relative cerebrovascular signal, with prominent cortical involvement, in rat brains assessed by functional magnetic resonance imaging.⁴

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1. Dugovic, C., Shelton, J.E., Aluisio, L.E., et al. Blockade of orexin-1 receptors attenuates orexin-2 receptor antagonism-induced sleep promotion in the rat. J. Pharmacol. Exp. Ther. 330(1), 142-151 (2009).

2. Faedo, S., Perdonà, E., Antolini, M., et al. Functional and binding kinetic studies make a distinction between OX1 and OX2 orexin receptor antagonists. Eur. J. Pharmacol. 692(1-3), 1-9 (2012).

3. Tran, D.T., Bonaventure, P., Hack, M., et al. Chimeric, mutant orexin receptors show key interactions between orexin receptors, peptides and antagonists. Eur. J. Pharmacol. 667(1-3), 120-128 (2011).

4. Gozzi, A., Turrini, G., Piccoli, L., et al. Functional magnetic resonance imaging reveals different neural substrates for the effects of orexin-1 and orexin-2 receptor antagonists. PLoS One 6(1), e16406 (2011).