Samelisant (SUVN-G3031), a potent, selective and orally active histamine H3 receptor inverse agonist for the potential treatment of narcolepsy: pharmacological and neurochemical characterisation.

RATIONALE: Samelisant (SUVN-G3031) is a potent and selective histamine H3 receptor (H3R) inverse agonist with good brain penetration and oral bioavailability. OBJECTIVES: Pharmacological and neurochemical characterisation to support the utility of Samelisant (SUVN-G3031) in the treatment of sleep-related disorders like narcolepsy. METHODS: Samelisant (SUVN-G3031) was tested in rat brain microdialysis studies for evaluation of modulation in histamine, dopamine and norepinephrine. Sleep EEG studies were carried out in orexin knockout mice to study the effects of Samelisant (SUVN-G3031) on the sleep-wake cycle and cataplexy. RESULTS: Samelisant (SUVN-G3031) has a similar binding affinity towards human (hH3R; Ki = 8.7 nM) and rat (rH3R; Ki = 9.8 nM) H3R indicating no inter-species differences. Samelisant (SUVN-G3031) displays inverse agonist activity and it exhibits very high selectivity towards H3R. Samelisant (SUVN-G3031) treatment in mice produced a dose-dependent increase in tele-methylhistamine levels indicating the activation of histaminergic neurotransmission. Apart from increasing the levels of histamine, Samelisant (SUVN-G3031) also modulates dopamine and norepinephrine levels in the cerebral cortex while it has no effects on dopamine levels in the striatum or nucleus accumbens. Treatment with Samelisant (SUVN-G3031; 10 and 30 mg/kg, p.o.) produced a significant increase in wakefulness with a concomitant decrease in NREM sleep in orexin knockout mice subjected to sleep EEG. Samelisant (SUVN-G3031) also produced a significant decrease in Direct REM sleep onset (DREM) episodes, demonstrating its anticataplectic effects in an animal model relevant to narcolepsy. Modulation in cortical levels of histamine, norepinephrine and dopamine provides the neurochemical basis for wake-promoting and anticataplectic effects observed in orexin knockout mice. CONCLUSIONS: Pre-clinical studies of Samelisant (SUVN-G3031) provide a strong support for utility in the treatment of sleep-related disorders related to EDS and is currently being evaluated in a phase 2 proof of concept study in the USA for the treatment of narcolepsy with and without cataplexy.

Simultaneous monitoring of electroencephalographic characteristics in animals subjected to behavioral tests: a preclinical investigation.

Drug-induced changes in electroencephalographic (EEG) characteristics in animals may be used to predict central activity of drugs in humans. Previous studies have established that drugs affect EEG characteristics in humans and rodents in a similar manner. However, there has been little work to establish correlations between drug effects on behavioral and EEG characteristics in rats. In the current study, we have simultaneously monitored EEG characteristics during a novel object recognition task (NORT) or open field (OF) test in rats. EEG was monitored using telemetric device from epidural and hippocampal regions during the choice trial in the NORT after treatment with scopolamine (0.1 mg/kg, intraperitoneal) alone or in combination with donepezil (0.3 mg/kg, subcutaneous). Power changes across spectral frequency bands during exploration of novel and familiar object were assessed separately. Amphetamine (2 mg/kg, intraperitoneal) was used to monitor effects on locomotor activity and EEG changes in the OF test. In the NORT, scopolamine impaired object recognition, but no differences were observed in the power densities across spectral bands during exploration of novel and familiar objects. Treatment with donepezil reversed scopolamine-induced cognitive impairment, and the power density in the theta frequency band was increased during exploration of the novel object. In OF, amphetamine increased locomotion and produced an overall decrease in the power densities of all frequency bands. Overall, the results indicate that EEG characteristics are closely related to behavioral changes in the NORT and OF in rodents.

Mechanistic evaluation of tapentadol in reducing the pain perception using in-vivo brain and spinal cord microdialysis in rats.

Role of monoamine neurotransmitters in the modulation of emotional and pain processing in spinal cord and brain regions is not well known. Tapentadol, a norepinephrine reuptake inhibitor with µ-opioid receptor agonistic activity has recently been introduced for the treatment of moderate to severe pain. The objective of the present study was to examine the effects of tapentadol on modulation of monoamines in the prefrontal cortex and dorsal horn using brain microdialysis. Tapentadol was administered intraperitoneally at 4.64-21.5mg/kg to male Wistar rats. Based on these results, 10mg/kg i.p. was chosen for spinal microdialysis in freely moving rats. Tapentadol produced significant and dose-dependent increase in cortical dopamine and norepinephrine levels with mean maximum increase of 600% and 300%, respectively. Treatment had no effect on cortical serotonin levels. In the dorsal horn, serotonin, dopamine and norepinephrine levels were significantly increased with mean maximum increases of 220%, 190% and 280%, respectively. Although the density of dopamine transporter is low in cortex, the increase of dopamine and norepinephrine levels in cortex could be mediated through the inhibition of norepinephrine transporter. In the dorsal horn, increase in norepinephrine levels could be due to inhibition of norepinephrine transporter in the spinal cord. Whereas, activation of opioids receptors in non-spinal regions might be responsible for increase in dopamine and serotonin levels. The results from current investigation suggest that clinical efficacy of tapentadol in neuropathic pain is mediated through the enhanced monoaminergic neurotransmission in the spinal cord and regions involved with emotional processing in brain.