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

  title={Biochemical and Electrophysiological Characterization of Almorexant, a Dual Orexin 1 Receptor (OX1)/Orexin 2 Receptor (OX2) Antagonist: Comparison with Selective OX1 and OX2 Antagonists},
  author={Pari Malherbe and Edilio Borroni and Emmanuel Pinard and Joseph G. Wettstein and Frédéric Knoflach},
  journal={Molecular Pharmacology},
  pages={618 - 631}
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… 

Kinetic properties of “dual” orexin receptor antagonists at OX1R and OX2R orexin receptors

The slow kinetics of the “dual” orexin receptor antagonists tested suggest that in vitro receptor occupancy may be longer lasting than would be predicted, and raises questions as to whether pharmacokinetic studies measuring plasma or brain levels of these antagonists are accurate reflections of receptor occupancy in vivo.

Mapping the Binding Pocket of Dual Antagonist Almorexant to Human Orexin 1 and Orexin 2 Receptors: Comparison with the Selective OX 1 Antagonist SB-674042 and the Selective OX 2 Antagonist N -Ethyl-2-[(6-methoxy-pyridin-3-yl)-(toluene-2-sulfonyl)-amino]-

Using site-directed mutagenesis, (cid:1) 2 -adrenergic-based OX 1 and OX 2 modeling, important molecular determinants of the ligand-binding pocket of OX said to be responsible for superficial OX receptor interactions of orexin-A are determined.

Mapping the Binding Pocket of Dual Antagonist Almorexant to Human Orexin 1 and Orexin 2 Receptors: Comparison with the Selective OX1 Antagonist SB-674042 and the Selective OX2 Antagonist N-Ethyl-2-[(6-methoxy-pyridin-3-yl)-(toluene-2-sulfonyl)-amino]-N-pyridin-3-ylmethyl-acetamide (EMPA)

Despite high similarities in the ligand-binding pockets of OX1 and OX2 and numerous aromatic/hydrophobic interactions, the local conformation of helix positions 3.32, 3.33, and 3.36 in transmembrane domain 3 and 45.51 in ECL2b provide the structural basis for pharmacologic selectivity between OX ones and two different antagonists for the same receptor.

Role of Orexin-1 Receptor Mechanisms on Compulsive Food Consumption in a Model of Binge Eating in Female Rats

Results indicate, for the first time, a major role of OX1R mechanisms in BE, suggesting that selective antagonism at OX2R could represent a novel pharmacological treatment for BE and possibly other eating disorders with a compulsive component.

The dual orexin receptor antagonist almorexant induces sleep and decreases orexin-induced locomotion by blocking orexin 2 receptors.

Almorexant specifically inhibits the actions of orexin A and dissociates very slowly from OX(2)R as measured functionally and in radioligand binding, and is sufficient to promote sleep in mice.

Distinct effects of IPSU and suvorexant on mouse sleep architecture

Testing suvorexant and IPSU in mice during the inactive phase when sleep is naturally more prevalent and when orexin levels are normally low suggested that OX2R preferring antagonists may have a reduced tendency for perturbing NREM/REM architecture in comparison with DORAs.

Study of human Orexin-1 and -2 G-protein-coupled receptors with novel and published antagonists by modeling, molecular dynamics simulations, and site-directed mutagenesis.

It is demonstrated how even small differences in the amino acid sequences of GPCRs can lead to significant differences in structure, antagonist binding affinity, and selectivity of these receptors.

Therapeutics development for addiction: Orexin-1 receptor antagonists




Blockade of Orexin-1 Receptors Attenuates Orexin-2 Receptor Antagonism-Induced Sleep Promotion in the Rat

Results indicate that blockade of OX2R is sufficient to initiate and prolong sleep, consistent with the hypothesis of a deactivation of the histaminergic system.

Distinct Recognition of OX1 and OX2Receptors by Orexin Peptides

The mutagenesis suggests that although the determinants required from orexin-A for binding to and activation of the receptor are highly conserved between the oxin receptor subtypes, the OX2receptor requires fewer determinants.

The signalling profile of recombinant human orexin-2 receptor.

SB‐334867‐A: the first selective orexin‐1 receptor antagonist

SB‐334867‐A is a non‐peptide OX1 selective receptor antagonist and neuropeptides Y and secretin displayed neither agonist nor antagonist properties in either cell‐line.

Direct Involvement of Orexinergic Systems in the Activation of the Mesolimbic Dopamine Pathway and Related Behaviors Induced by Morphine

Findings provide new evidence that orexin-containing neurons in the VTA are directly implicated in the rewarding effect and hyperlocomotion induced by morphine through activation of the mesolimbic dopamine pathway in rodents.

Selective stimulation of orexin receptor type 2 promotes wakefulness in freely behaving rats

Characterisation of the binding of [3H]‐SB‐674042, a novel nonpeptide antagonist, to the human orexin‐1 receptor

Calcium mobilisation studies showed that SB‐334867, SB‐408124 and SB‐410220 are all functional antagonists of the OX1 receptor, with potencies in line with their affinities, as measured in the radioligand binding assays, and with approximately 50‐fold selectivity over the orexin‐2 receptor.

N-acyl 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline: the first orexin-2 receptor selective non-peptidic antagonist.

Arousal effect of orexin A depends on activation of the histaminergic system

  • Zhi-Li HuangW. Qu O. Hayaishi
  • Biology, Psychology
    Proceedings of the National Academy of Sciences of the United States of America
  • 2001
Findings strongly indicate that the arousal effect of orexin A depends on the activation of histaminergic neurotransmission mediated by H1R.