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-rela...
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Published in | Psychopharmacology Vol. 238; no. 6; pp. 1495 - 1511 |
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Main Authors | , , , , , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
Berlin/Heidelberg
Springer Berlin Heidelberg
01.06.2021
Springer Springer Nature B.V |
Subjects | |
Online Access | Get full text |
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Summary: | 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;
K
i
= 8.7 nM) and rat (rH3R;
K
i
= 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. |
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Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 |
ISSN: | 0033-3158 1432-2072 |
DOI: | 10.1007/s00213-021-05779-x |