Pharmacological characterization of the orexin/hypocretin receptor agonist Nag 26

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Rinne , M K , Leino , T O , Turku , A , Turunen , P M , Steynen , Y , Xhaard , H , Wallen , E A A & Kukkonen , J P 2018 , ' Pharmacological characterization of the orexin/hypocretin receptor agonist Nag 26 ' , European Journal of Pharmacology , vol. 837 , pp. 137-144 . https://doi.org/10.1016/j.ejphar.2018.09.003

Title: Pharmacological characterization of the orexin/hypocretin receptor agonist Nag 26
Author: Rinne, Maiju K.; Leino, Teppo O.; Turku, Ainoleena; Turunen, Pauli M.; Steynen, Yana; Xhaard, Henri; Wallen, Erik A. A.; Kukkonen, Jyrki P.
Other contributor: University of Helsinki, Faculty of Pharmacy
University of Helsinki, Faculty of Pharmacy
University of Helsinki, Pharmaceutical Design and Discovery group
University of Helsinki, Medicum
University of Helsinki, Faculty of Pharmacy
University of Helsinki, Faculty of Pharmacy
University of Helsinki, Jyrki Kukkonen / Principal Investigator












Date: 2018-10-15
Language: eng
Number of pages: 8
Belongs to series: European Journal of Pharmacology
ISSN: 0014-2999
DOI: https://doi.org/10.1016/j.ejphar.2018.09.003
URI: http://hdl.handle.net/10138/305214
Abstract: One promising series of small-molecule orexin receptor agonists has been described, but the molecular pharmacological properties, i.e. ability and potency to activate the different orexin receptor-regulated signal pathways have not been reported for any of these ligands. We have thus here assessed these properties for the most potent ligand of the series, 4'-methoxy-N,N-dimethyl-3'4N-(3-{[2-(3-methylbenzamido)ethyl]amino}phenyl sulfamoy1]-(1,1'-biphenyl)-3-carboxamide (Nag 26). Chinese hamster ovary-K1 cells expressing human orexin receptor subtypes OX1 and OX2 were used. Ca2+ elevation and cell viability and death were assessed by fluorescent methods, the extracellular signal-regulated kinase pathway by a luminescent Elk-1 reporter assay, and phospholipase C and adenylyl cyclase activities by radioactive methods. The data suggest that for the G(q)-dependent responses, Ca2+, phospholipase C and Elk-1, Nag 26 is a full agonist for both receptors, though of much lower potency. However, saturation was not always reached for OX1, partially due to Nag 26s low solubility and partially because the response decreased at high concentrations. The latter occurs in the same range as some reduction of cell viability, which is independent of orexin receptors. Based on the EC50, Nag 26 was OX2 selective by 20-200 fold in different assays, with some indication of biased agonism (as compared to orexin-A). Nag 26 is a potent orexin receptor agonist with a largely similar pharmacological profile as orexin-A. However, its weaker potency (low-mid micromolar) and low water solubility as well as the non-specific effect in the mid-micromolar range may limit its usefulness under physiological conditions.
Subject: Orexin
Calcium
Phospholipase C
cAMP
Cell death
ERK
ACTIVATED PROTEIN-KINASE
OREXIN TYPE-2 RECEPTOR
HAMSTER OVARY CELLS
OX1 RECEPTOR
NARCOLEPSY
SLEEP
MICE
WAKEFULNESS
APOPTOSIS
GENE
317 Pharmacy
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