Functional and binding kinetic studies make a distinction between OX1 and OX2 orexin receptor antagonists

被引：18

作者：

Faedo, Stefania ^{[1
]}

Perdona, Elisabetta ^{[1
]}

Antolini, Marinella ^{[1
]}

di Fabio, Romano ^{[1
]}

Pich, Emilio Merlo ^{[1
]}

Corsi, Mauro ^{[1
]}

机构：

[1] GlaxoSmithKline, Neurosci Ctr Excellence Drug Discovery, Med Res Ctr, I-37135 Verona, Italy

来源：

EUROPEAN JOURNAL OF PHARMACOLOGY | 2012年 / 692卷 / 1-3期

关键词：

Orexin-1; receptor; Orexin-2; Orexin agonist; Orexin receptor antagonists; IP1; accumulation; PROTEIN-COUPLED RECEPTORS; PHARMACOLOGICAL CHARACTERIZATION; TYPE-2; RECEPTORS; SLEEP DISORDERS; RAT-BRAIN; EXPRESSION; SYSTEM; HYPOCRETIN/OREXIN; DISCOVERY; PROMOTION;

D O I：

10.1016/j.ejphar.2012.07.007

中图分类号：

R9 [药学];

学科分类号：

1007 ;

摘要：

In this work the pharmacology and the receptor kinetics of the following orexin receptor antagonists SB-649868, ACT-078573, JNJ-10397049, MK-6096 and Roche-Cp were evaluated at human OX1 and OX2 orexin receptors by using functional and receptor binding assays. Kinetic analysis of the unlabeled ligands was carried out by indirect measurement according to the Motulski and Mahan's method as opposed to the direct measure by using labeled test compounds. All compounds antagonized orexin-A-induced inositol 1 phosphate (IP1) accumulation with the following pK(B) values: SB-649868 (OX1 =9.67; OX2=9.64), ACT-078573 (OX1=8.44; OX2=9.02), JNJ-10397049 (OX1=5.97; OX2=8.35), MK-6096 (OX1=9.13; OX2=9.79) and Roche-Cp (OX1=7.18; OX2=8.83). They displaced the [H-3]ACT-078573 receptor binding with the following pK(i), values: SB-649868 (OX1=9.27; OX2=8.91), ACT-078573 (OX1=7.80; OX2=9.12), JNJ-10397049 (OX1 =5.18; OX2=8.10), MK-6096 (OX1 =8.39; OX2=8.90) and Roche-Cp (OX1=6.65; OX2=8.54). From dissociation kinetic studies using [H-3]ACT-078573, the calculated long half-life, (t(1/2)) supported the non-surmountability profile of SB-649868 (t(1/2)=35.91 min) at OX1 orexin receptor. Similarly, the long or moderately long t(1/2) values for ACT-078573 at OX2 orexin receptor t(1/2)=69.71 min), MK-6096 t(1/2)=17.70 min), SB-649868 (t(1/2)=8.09 min) and Roche-Cp (t(1/2)=5.79 min) sustained their non-surmountable profile. JNJ-10397049 showed short t(1/2) values at both receptor subtypes (OX1 t(1/2)=0.19 min; OX2 t(1/2)=0.60 min) with surmountable antagonism. (C) 2012 Elsevier B.V. All rights reserved.

引用

页码：1 / 9

页数：9

共 36 条

[1] Heterologous expression of G protein-coupled receptors in U-2OS osteosarcoma cells [J].

Ames, RS ;

Nuthulaganti, P ;

Fornwald, JA ;

Shabon, U ;

van-der-Keyl, HK ;

Elshourbagy, NA .

RECEPTORS & CHANNELS, 2004, 10 (3-4) :117-124

[2] BacMam recombinant Baculoviruses in G protein-coupled receptor drug discovery [J].

Ames, RS ;

Fornwald, JA ;

Nuthulaganti, P ;

Trill, JJ ;

Foley, JJ ;

Buckley, PT ;

Kost, TA ;

Wu, ZN ;

Romanos, MA .

RECEPTORS & CHANNELS, 2004, 10 (3-4) :99-107

[3] SOME QUANTITATIVE USES OF DRUG ANTAGONISTS [J].

ARUNLAKSHANA, O ;

SCHILD, HO .

BRITISH JOURNAL OF PHARMACOLOGY AND CHEMOTHERAPY, 1959, 14 (01) :48-58

[4]

Breslin M.J., 2008, Pyridylpiperidine orerexin receptorantagonists, Patent No. [WO2008/147518A1, 2008147518]

[5] Promotion of sleep by targeting the orexin system in rats, dogs and humans [J].

Brisbare-Roch, Catherine ;

Dingemanse, Jasper ;

Koberstein, Ralf ;

Hoever, Petra ;

Aissaoui, Hamed ;

Flores, Susan ;

Mueller, Celia ;

Nayler, Oliver ;

van Gerven, Joop ;

de Haas, Sanne L. ;

Hess, Patrick ;

Qiu, Changbin ;

Buchmann, Stephan ;

Scherz, Michael ;

Weller, Thomas ;

Fischli, Walter ;

Clozel, Martine ;

Jenck, Francois .

NATURE MEDICINE, 2007, 13 (02) :150-155

[6]

CHENG Y, 1973, BIOCHEM PHARMACOL, V22, P3099

[7] Protein distribution of the orexin-2 receptor in the rat central nervous system [J].

Cluderay, JE ;

Harrison, DC ;

Hervieu, GJ .

REGULATORY PEPTIDES, 2002, 104 (1-3) :131-144

[8] The hypocretins: Hypothalamus-specific peptides with neuroexcitatory activity [J].

De Lecea, L ;

Kilduff, TS ;

Peyron, C ;

Gao, XB ;

Foye, PE ;

Danielson, PE ;

Fukuhara, C ;

Battenberg, ELF ;

Gautvik, VT ;

Bartlett, FS ;

Frankel, WN ;

van den Pol, AN ;

Bloom, FE ;

Gautvik, KM ;

Sutcliffe, JG .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1998, 95 (01) :322-327

[9] Discovery process and pharmacological characterization of a novel dual orexin 1 and orexin 2 receptor antagonist useful for treatment of sleep disorders [J].

Di Fabio, Romano ;

Pellacani, Annalisa ;

Faedo, Stefania ;

Roth, Adelheid ;

Piccoli, Laura ;

Gerrard, Philip ;

Porter, Rod A. ;

Johnson, Christopher N. ;

Thewlis, Kevin ;

Donati, Daniele ;

Stasi, Luigi ;

Spada, Simone ;

Stemp, Geoffrey ;

Nash, David ;

Branch, Clive ;

Kindon, Leanda ;

Massagrande, Mario ;

Poffe, Alessandro ;

Braggio, Simone ;

Chiarparin, Elisabetta ;

Marchioro, Carla ;

Ratti, Emiliangelo ;

Corsi, Mauro .

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2011, 21 (18) :5562-5567

[10] Orexin receptor expression in human adipose tissue: effects of orexin-A and orexin-B [J].

Digby, J. E. ;

Chen, J. ;

Tang, J. Y. ;

Lehnert, H. ;

Matthews, R. N. ;

Randeva, H. S. .

JOURNAL OF ENDOCRINOLOGY, 2006, 191 (01) :129-136

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