التفاصيل البيبلوغرافية
| العنوان: |
Pharmacological characterization of the orexin/hypocretin receptor agonist Nag 26 |
| المؤلفون: |
Rinne, Maiju K., Leino, Teppo O., Turku, Ainoleena, Turunen, Pauli M., Steynen, Yana, Xhaard, Henri, Wallen, Erik A. A., Kukkonen, Jyrki P. |
| المساهمون: |
Faculty of Pharmacy, Division of Pharmaceutical Chemistry and Technology, Veterinary Biosciences, Departments of Faculty of Veterinary Medicine, Pharmaceutical Design and Discovery group, Medicum, Department of Physiology, Veterinary Biochemistry and Cell Biology, Henri Xhaard / Principal Investigator, Computational Adme, Drug Research Program, Erik Wallen / Principal Investigator, Jyrki Kukkonen / Principal Investigator, Medicinal Chemistry research group |
| بيانات النشر: |
Elsevier Scientific Publ. Co |
| سنة النشر: |
2019 |
| المجموعة: |
Helsingfors Universitet: HELDA – Helsingin yliopiston digitaalinen arkisto |
| مصطلحات موضوعية: |
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 |
| الوصف: |
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. ; Peer reviewed |
| نوع الوثيقة: |
article in journal/newspaper |
| وصف الملف: |
application/pdf |
| اللغة: |
English |
| العلاقة: |
Santeri Suokas, Marja Peltola and Jouni Oksanen (Biochemistry and Cell Biology, Department of Veterinary Biosciences, University of Helsinki) are gratefully acknowledged for technical assistance with the experiments, and Kaj-Roger Hurme (Instrument Centre of Faculty of Agriculture and Forestry, University of Helsinki) and Raija Savolainen (Institute of Biotechnology, University of Helsinki) for all help with the liquid scintillation counting and luminescence measurements, respectively. This work was supported by the European Union (FP7-HEALTHproject GLORIA [# 602919]), the Magnus Ehrnrooth Foundation, the Finnish Cultural Foundation, the Orion Research Foundation, the Liv & Halsa Foundation, and the Doctoral Program in Drug Research of the University of Helsinki.; 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.2018.09.003Test; ORCID: /0000-0003-0959-7221/work/49162309; ORCID: /0000-0003-2582-7971/work/49162603; ORCID: /0000-0002-3129-1678/work/49160715; ORCID: /0000-0002-6989-1564/work/63349243; ORCID: /0000-0003-3218-2841/work/68616121; http://hdl.handle.net/10138/305214Test; aff2e1b3-c4b3-4caf-a9e3-98c8277aa516; 85053081769; 000444963400016 |
| الإتاحة: |
http://hdl.handle.net/10138/305214Test |
| حقوق: |
cc_by_nc_nd ; info:eu-repo/semantics/openAccess ; openAccess |
| رقم الانضمام: |
edsbas.C6500E07 |
| قاعدة البيانات: |
BASE |
