Samelisant (free base)

Samelisant (SUVN-G3031) free base is a potent and selective histamine H3 receptor (H3R) inverse agonist with good brain penetration and oral bioavailability. Samelisant free base has a similar binding affinity towards human (hH3R; K_i=8.7 nM) and rat (rH3R;K_i=9.8 nM) H3R indicating no inter-species differences. Samelisant free base can be used for the research of sleep-related disorders^[1]. In Vitro: Samelisant free base displays inverse agonist activity and it exhibits very high selectivity towards H3R. The pEC₅₀ value of histamine (8.5) for human H3 receptor increases to 8.2, 7.3 and 6.2 after treatment with 1, 10 and 100 nM of Samelisant, respectively. The pEC₅₀ value of histamine (8.2) for rat H3 receptor increases to 7.9, 7.4 and 6.4 after treatment with 1, 10 and 100 nmol/L of Samelisant, respectively^[1].
Samelisant free base binds to the orthosteric site in a reversible manner with K_b values of 1.3 nM and 1.1 nM deduced from pA₂ value for human and rat H3R, respectively^[1].
Samelisant free base also modulates dopamine and norepinephrine levels in the cerebral cortex while it has no effects on dopamine levels in the striatum or nucleus accumbens^[1]. In Vivo: Treatment with Samelisant (10 and 30 mg/kg, p.o.) free base produces a significant increase in wakefulness with a concomitant decrease in non-rapid eye movement sleep (NREM) sleep in orexin knockout mice subjected to sleep electroencephalography (EEG)^[1].
Samelisant free base also produces a significant decrease in direct rapid eye movement (REM) sleep onset (DREM) episodes, demonstrating its anticataplectic effects in an animal model relevant to narcolepsy^[1].
Samelisant free base treatment in mice produces a dose-dependent increase in tele-methylhistamine levels indicating the activation of histaminergic neurotransmission^[1].