Samelisant (SUVN-G3031), a potent, selective and orally active histamine H3 receptor inverse agonist for the potential treatment of narcolepsy: pharmacological and neurochemical characterisation
| Autor: | Surendra Petlu, Rajesh Kumar Badange, Ramkumar Subramanian, Nageswara Rao Muddana, Venkatesh Kamuju, Saivishal Daripelli, Shinde Anil Karbhari, Venkat Reddy Mekala, Gopinadh Bhyrapuneni, Ramakrishna Nirogi, Vijay Benade, Venkat Jasti, Pradeep Jayarajan |
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| Rok vydání: | 2020 |
| Předmět: |
Male
Cataplexy Morpholines Pharmacology Histamine Agonists 03 medical and health sciences Mice 0302 clinical medicine Neurochemical Piperidines Dopamine medicine Inverse agonist Animals Humans Rats Wistar Wakefulness Narcolepsy Mice Knockout Orexins Chemistry Methylhistamines Histaminergic Electroencephalography medicine.disease 030227 psychiatry Orexin Rats Mice Inbred C57BL Histamine H3 receptor medicine.symptom Sleep 030217 neurology & neurosurgery medicine.drug Histamine |
| Zdroj: | Psychopharmacology. 238(6) |
| ISSN: | 1432-2072 |
| Popis: | Samelisant (SUVN-G3031) is a potent and selective histamine H3 receptor (H3R) inverse agonist with good brain penetration and oral bioavailability. Pharmacological and neurochemical characterisation to support the utility of Samelisant (SUVN-G3031) in the treatment of sleep-related disorders like narcolepsy. 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. 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. 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. |
| Databáze: | OpenAIRE |
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