Orexin receptor agonist Yan 7874 is a weak agonist of orexin/hypocretin receptors and shows orexin receptor-independent cytotoxicity

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Turku , A , Rinne , M K , af Gennas , G B , Xhaard , H , Lindholm , D & Kukkonen , J P 2017 , ' Orexin receptor agonist Yan 7874 is a weak agonist of orexin/hypocretin receptors and shows orexin receptor-independent cytotoxicity ' , PLoS One , vol. 12 , no. 5 , 0178526 . https://doi.org/10.1371/journal.pone.0178526

Title: Orexin receptor agonist Yan 7874 is a weak agonist of orexin/hypocretin receptors and shows orexin receptor-independent cytotoxicity
Author: Turku, Ainoleena; Rinne, Maiju K.; af Gennas, Gustav Boije; Xhaard, Henri; Lindholm, Dan; Kukkonen, Jyrki P.
Contributor: University of Helsinki, Faculty of Pharmacy
University of Helsinki, Faculty of Pharmacy
University of Helsinki, Faculty of Pharmacy
University of Helsinki, University of Helsinki
University of Helsinki, Medicum
University of Helsinki, University of Helsinki
Date: 2017-06-02
Language: eng
Number of pages: 15
Belongs to series: PLoS One
ISSN: 1932-6203
URI: http://hdl.handle.net/10138/195933
Abstract: Two promising lead structures of small molecular orexin receptor agonist have been reported, but without detailed analyses of the pharmacological properties. One of them, 1(3,4-dichloropheny1)-242-imino-3-(4-methylbenzy1)-2,3-dihydro-1H-benzo[climidazol-1-yl] ethan-1-ol (Yan 7874), is commercially available, and we set out to analyze its properties. As test system we utilized human OX1 and OX2 orexin receptor -expressing Chinese hamster ovary (CHO) K1 cells as well as control CHO-K1 and neuro-2a neuroblastoma cells. Gq-coupling was assessed by measurement of intracellular Ca2+ and phospholipase C activity, and the coupling to G(i) and G(s) by adenylyl cyclase inhibition and stimulation, respectively. At concentrations above 1 pM, strong Ca' and low phospholipase C responses to Yan 7874 were observed in both OX1- and OX2-expressing cells. However, a major fraction of the response was not mediated by orexin receptors, as determined utilizing the nonselective orexin receptor antagonist N-biphenyl-2-y1-1-{[(1-methyl-1H-benzimidazol-2-y1) sulfanyl]acetyl}-L-prolinamide (TCS 1102) as well as control CHO-K1 cells. Yan 7874 did not produce any specific adenylyl cyclase response. Some experiments suggested an effect on cell viability by Yan 7874, and we thus analyzed this. Within a few hours of exposure, Yan 7874 markedly changed cell morphology (shrunken, rich in vacuoles), reduced growth, promoted cell detachment, and induced necrotic cell death. The effect was equal in cells expressing orexin receptors or not. Thus, Yan 7874 is a weak partial agonist of orexin receptors. It also displays strong off -target effects in the same concentration range, culminating in necrotic cell demise. This makes Yan 7874 unsuitable as orexin receptor agonist.
Subject: HAMSTER OVARY CELLS
OX1 RECEPTOR
APOPTOSIS
ANTAGONISTS
NARCOLEPSY
WAKEFULNESS
NECROSIS
CANCER
DEATH
MODEL
317 Pharmacy
3111 Biomedicine
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