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Molecular Pharmacology

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Research ArticleArticle

Biochemical and Electrophysiological Characterization of Almorexant, a Dual Orexin 1 Receptor (OX1)/Orexin 2 Receptor (OX2) Antagonist: Comparison with Selective OX1 and OX2 Antagonists

Pari Malherbe, Edilio Borroni, Emmanuel Pinard, Joseph G. Wettstein and Frédéric Knoflach
Molecular Pharmacology September 2009, 76 (3) 618-631; DOI: https://doi.org/10.1124/mol.109.055152
Pari Malherbe
CNS Research (P.M., E.B., J.G.W., F.K.) and Chemistry Discovery (E.P.), F. Hoffmann-La Roche Ltd., Basel, Switzerland
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Edilio Borroni
CNS Research (P.M., E.B., J.G.W., F.K.) and Chemistry Discovery (E.P.), F. Hoffmann-La Roche Ltd., Basel, Switzerland
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Emmanuel Pinard
CNS Research (P.M., E.B., J.G.W., F.K.) and Chemistry Discovery (E.P.), F. Hoffmann-La Roche Ltd., Basel, Switzerland
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Joseph G. Wettstein
CNS Research (P.M., E.B., J.G.W., F.K.) and Chemistry Discovery (E.P.), F. Hoffmann-La Roche Ltd., Basel, Switzerland
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Frédéric Knoflach
CNS Research (P.M., E.B., J.G.W., F.K.) and Chemistry Discovery (E.P.), F. Hoffmann-La Roche Ltd., Basel, Switzerland
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Abstract

Recent preclinical and clinical research has shown that almorexant promotes sleep in animals and humans without disrupting the sleep architecture. Here, the pharmacology and kinetics of [3H]almorexant binding to human orexin 1 receptor (OX1)- and human orexin 2 receptor (OX2)-human embryonic kidney 293 membranes were characterized and compared with those of selective OX1 and OX2 antagonists, including 1-(5-(2-fluoro-phenyl)-2-methyl-thiazol-4-yl)-1-((S)-2-(5-phenyl-(1,3,4)oxadiazol-2-ylmethyl)-pyrrolidin-1-yl)-methanone (SB-674042), 1-(6,8-difluoro-2-methyl-quinolin-4-yl)-3-(4-dimethylamino-phenyl)-urea (SB-408124), and N-ethyl-2-[(6-methoxy-pyridin-3-yl)-(toluene-2-sulfonyl)-amino]-N-pyridin-3-ylmethyl-acetamide (EMPA). The effect of these antagonists was also examined in vitro on the spontaneous activity of rat ventral tegmental area (VTA) dopaminergic neurons. [3H]Almorexant bound to a single saturable site on hOX1 and hOX2 with high affinity (Kd of 1.3 and 0.17 nM, respectively). In Schild analyses using the [3H]inositol phosphates assay, almorexant acted as a competitive antagonist at hOX1 and as a noncompetitive-like antagonist at hOX2. In binding kinetic analyses, [3H]almorexant had fast association and dissociation rates at hOX1, whereas it had a fast association rate and a remarkably slow dissociation rate at hOX2. In the VTA, orexin-A potentiated the basal firing frequency to 175 ± 17% of control in approximately half of the neurons tested. In the presence of 1 μM SB-674042 or SB-408124, the effect of orexin-A was only partially antagonized. However, in the presence of 1 μM EMPA or 1 μM almorexant, the effect of orexin-A was completely antagonized. In conclusion, almorexant exhibited a noncompetitive and long-lasting pseudo-irreversible mode of antagonism as a result of its very slow rate of dissociation from OX2. The electrophysiology data suggest that OX2 might be more important than OX1 in mediating the effect of orexin-A on slow-firing of VTA dopaminergic neurons.

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Molecular Pharmacology: 76 (3)
Molecular Pharmacology
Vol. 76, Issue 3
1 Sep 2009
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Research ArticleArticle

Biochemical and Electrophysiological Characterization of Almorexant, a Dual Orexin 1 Receptor (OX1)/Orexin 2 Receptor (OX2) Antagonist: Comparison with Selective OX1 and OX2 Antagonists

Pari Malherbe, Edilio Borroni, Emmanuel Pinard, Joseph G. Wettstein and Frédéric Knoflach
Molecular Pharmacology September 1, 2009, 76 (3) 618-631; DOI: https://doi.org/10.1124/mol.109.055152

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Research ArticleArticle

Biochemical and Electrophysiological Characterization of Almorexant, a Dual Orexin 1 Receptor (OX1)/Orexin 2 Receptor (OX2) Antagonist: Comparison with Selective OX1 and OX2 Antagonists

Pari Malherbe, Edilio Borroni, Emmanuel Pinard, Joseph G. Wettstein and Frédéric Knoflach
Molecular Pharmacology September 1, 2009, 76 (3) 618-631; DOI: https://doi.org/10.1124/mol.109.055152
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