Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Discovery Of An Orexin Receptor Positive Potentiator.

ABSTRACT: The orexin neurohormones control a variety of important physiological processes by signaling through two related G protein-coupled receptors, including appetite and feeding, wakefulness and energy homeostasis. Pharmacological manipulation of orexin signaling is an important goal. Here we describe the isolation of orexin receptor ligands from a library of microarray-displayed peptoids via a novel two-color, cell-based screen. Functional analysis of derivatives of these "hits" resulted in the development of moderate potency, low molecular weight receptor antagonists. Moreover, further optimization efforts resulted in the fortuitous discovery of a compound that positively potentiates the activity of the receptor. This compound is the first small molecule reported to up-regulate orexin signaling.

SUBMITTER: Lee J

PROVIDER: S-EPMC3883070 | biostudies-literature | 2010 Jul

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Publications

Discovery Of An Orexin Receptor Positive Potentiator.

Lee Jiyong J Reddy M Muralidhar MM Kodadek Thomas T

Chemical science 20100701 1

The orexin neurohormones control a variety of important physiological processes by signaling through two related G protein-coupled receptors, including appetite and feeding, wakefulness and energy homeostasis. Pharmacological manipulation of orexin signaling is an important goal. Here we describe the isolation of orexin receptor ligands from a library of microarray-displayed peptoids via a novel two-color, cell-based screen. Functional analysis of derivatives of these "hits" resulted in the deve ...[more]

PMID: 24409338

Similar Datasets

Discovery of Arylsulfonamides as Dual Orexin Receptor Agonists.

Project description:Loss of orexin-producing neurons results in narcolepsy with cataplexy, and orexin agonists have been shown to increase wakefulness and alleviate narcolepsy symptoms in animal models. Several OX2R agonists have been reported but with little or no activity at OX1R. We conducted structure-activity relationship studies on the OX2R agonist YNT-185 (2) and discovered dual agonists such as RTOXA-43 (40) with EC50's of 24 nM at both OX2R and OX1R. Computational modeling studies based on the agonist-bound OX2R cryogenic electron microscopy structures showed that 40 bound in the same binding pocket and interactions of the pyridylmethyl group of 40 with OX1R may have contributed to its high OX1R potency. Intraperitoneal injection of 40 increased time awake, decreased time asleep, and increased sleep/wake consolidation in 12-month old mice. This work provides a promising dual small molecule agonist and supports development of orexin agonists as potential treatments for orexin-deficient disorders such as narcolepsy.

| S-EPMC8994207 | biostudies-literature

RNA Sequencing: A Potentiator of Discovery-based Research.

Project description: Not available

| S-EPMC6827071 | biostudies-literature

Discovery of TAK-925 as a Potent, Selective, and Brain-Penetrant Orexin 2 Receptor Agonist.

Project description:TAK-925, a potent, selective, and brain-penetrant orexin 2 receptor (OX2R) agonist, [methyl (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)piperidine-1-carboxylate, 16], was identified through the optimization of compound 2, which was discovered by a high throughput screening (HTS) campaign. Subcutaneous administration of compound 16 produced wake-promoting effects in mice during the sleep phase. Compound 16 (TAK-925) is being developed for the treatment of narcolepsy and other related disorders.

| S-EPMC8919389 | biostudies-literature

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

Project description: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-dichlorophenyl)-2-[2-imino-3-(4-methylbenzyl)-2,3-dihydro-1H-benzo[d]imidazol-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 Gi and Gs by adenylyl cyclase inhibition and stimulation, respectively. At concentrations above 1 ?M, strong Ca2+ 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 non-selective orexin receptor antagonist N-biphenyl-2-yl-1-{[(1-methyl-1H-benzimidazol-2-yl)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.

| S-EPMC5456073 | biostudies-literature

A molecular network map of orexin-orexin receptor signaling system.

Project description:Orexins are excitatory neuropeptides, which are predominantly associated with feeding behavior, sleep-wake cycle and energy homeostasis. The orexinergic system comprises of HCRTR1 and HCRTR2, G-protein-coupled receptors of rhodopsin family and the endogenous ligands processed from HCRT pro-hormone, Orexin A and Orexin B. These neuropeptides are biosynthesized by the orexin neurons present in the lateral hypothalamus area, with dense projections to other brain regions. The orexin-receptor signaling is implicated in various metabolic as well as neurological disorders, making it a promising target for pharmacological interventions. However, there is limited information available on the collective representation of the signal transduction pathways pertaining to the orexin-orexin receptor signaling system. Here, we depict a compendium of the Orexin A/B stimulated reactions in the form of a basic signaling pathway map. This map catalogs the reactions into five categories: molecular association, activation/inhibition, catalysis, transport, and gene regulation. A total of 318 downstream molecules were annotated adhering to the guidelines of NetPath curation. This pathway map can be utilized for further assessment of signaling events associated with orexin-mediated physiological functions and is freely available on WikiPathways, an open-source pathway database ( https://www.wikipathways.org/index.php/Pathway:WP5094 ).

| S-EPMC10030760 | biostudies-literature

Orexin signaling via the orexin 1 receptor mediates operant responding for food reinforcement.

Project description:Orexin (hypocretin) signaling is implicated in drug addiction and reward, but its role in feeding and food-motivated behavior remains unclear.We investigated orexin's contribution to food-reinforced instrumental responding using an orexin 1 receptor (Ox1r) antagonist, orexin -/- (OKO) and littermate wildtype (WT) mice, and RNAi-mediated knockdown of orexin. C57BL/6J (n = 76) and OKO (n = 39) mice were trained to nose poke for food under a variable ratio schedule of reinforcement. After responding stabilized, a progressive ratio schedule was initiated to evaluate motivation to obtain food reinforcement.Blockade of Ox1r in C57BL/6J mice impaired performance under both the variable ratio and progressive ratio schedules of reinforcement, indicating impaired motivational processes. In contrast, OKO mice initially demonstrated a delay in acquisition but eventually achieved levels of responding similar to those observed in WT animals. Moreover, OKO mice did not differ from WT mice under a progressive ratio schedule, indicating delayed learning processes but no motivational impairments. Considering the differences between pharmacologic blockade of Ox1r and the OKO mice, animals with RNAi mediated knockdown of orexin were then generated and analyzed to eliminate possible developmental effects of missing orexin. Orexin gene knockdown in the lateral hypothalamus in C57BL/6J mice resulted in blunted performance under both the variable ratio and progressive ratio schedules, resembling data obtained following Ox1r antagonism.The behavior seen in OKO mice likely reflects developmental compensation often seen in mutant animals. These data suggest that activation of the Ox1r is a necessary component of food-reinforced responding, motivation, or both in normal mice.

| S-EPMC2849869 | biostudies-literature

Discovery of Oxazolobenzimidazoles as Positive Allosteric Modulators for the mGluR2 Receptor.

Project description:Novel oxazolobenzimidazoles are described as potent and selective positive allosteric modulators of the metabotropic glutamate receptor 2. The discovery of this class and optimization of its physical and pharmacokinetic properties led to the identification of potent and orally bioavailable compounds (20 and 21) as advanced leads. Compound 20 (TBPCOB) was shown to have robust activity in a PCP-induced hyperlocomotion model in rat, an assay responsive to clinical antipsychotic treatments for schizophrenia.

| S-EPMC4007895 | biostudies-other

OX1 and OX2 orexin/hypocretin receptor pharmacogenetics.

Project description:Orexin/hypocretin peptide mutations are rare in humans. Even though human narcolepsy is associated with orexin deficiency, this is only extremely rarely due to mutations in the gene coding prepro-orexin, the precursor for both orexin peptides. In contrast, coding and non-coding variants of the OX1 and OX2 orexin receptors have been identified in many human populations; sometimes, these have been associated with disease phenotype, although most confer a relatively low risk. In most cases, these studies have been based on a candidate gene hypothesis that predicts the involvement of orexins in the relevant pathophysiological processes. In the current review, the known human OX1/HCRTR1 and OX2/HCRTR2 genetic variants/polymorphisms as well as studies concerning their involvement in disorders such as narcolepsy, excessive daytime sleepiness, cluster headache, polydipsia-hyponatremia in schizophrenia, and affective disorders are discussed. In most cases, the functional cellular or pharmacological correlates of orexin variants have not been investigated-with the exception of the possible impact of an amino acid 10 Pro/Ser variant of OX2 on orexin potency-leaving conclusions on the nature of the receptor variant effects speculative. Nevertheless, we present perspectives that could shape the basis for further studies. The pharmacology and other properties of the orexin receptor variants are discussed in the context of GPCR signaling. Since orexinergic therapeutics are emerging, the impact of receptor variants on the affinity or potency of ligands deserves consideration. This perspective (pharmacogenetics) is also discussed in the review.

| S-EPMC4018553 | biostudies-literature

Orexin/hypocretin receptor signalling: a functional perspective.

Project description:Multiple homeostatic systems are regulated by orexin (hypocretin) peptides and their two known GPCRs. Activation of orexin receptors promotes waking and is essential for expression of normal sleep and waking behaviour, with the sleep disorder narcolepsy resulting from the absence of orexin signalling. Orexin receptors also influence systems regulating appetite/metabolism, stress and reward, and are found in several peripheral tissues. Nevertheless, much remains unknown about the signalling pathways and targets engaged by native receptors. In this review, we integrate knowledge about the orexin receptor signalling capabilities obtained from studies in expression systems and various native cell types (as presented in Kukkonen and Leonard, this issue of British Journal of Pharmacology) with knowledge of orexin signalling in different tissues. The tissues reviewed include the CNS, the gastrointestinal tract, the pituitary gland, pancreas, adrenal gland, adipose tissue and the male reproductive system. We also summarize the findings in different native and recombinant cell lines, especially focusing on the different cascades in CHO cells, which is the most investigated cell line. This reveals that while a substantial gap exists between what is known about orexin receptor signalling and effectors in recombinant systems and native systems, mounting evidence suggests that orexin receptor signalling is more diverse than originally thought. Moreover, rather than being restricted to orexin receptor 'overexpressing' cells, this signalling diversity may be utilized by native receptors in a site-specific manner.

| S-EPMC3904253 | biostudies-literature

Optical probing of orexin/hypocretin receptor antagonists.

Project description:Study objectivesThe present study investigated the function of Hypocretin (Hcrt or Orexin/OX) receptor antagonists in sleep modulation and memory function with optical methods in transgenic mice.MethodsWe used Hcrt-IRES-Cre knock-in mice and AAV vectors expressing channelrhodopsin-2 (ChR2) to render Hcrt neurons sensitive to blue light stimulation. We optogenetically stimulated Hcrt neurons and measured latencies to wakefulness in the presence or absence of OX1/2R antagonists and Zolpidem. We also examined endogenous Hcrt neuronal activity with fiber photometry. Changes in memory after optogenetic sleep disruption were evaluated by the novel object recognition test (NOR) and compared for groups treated with vehicle, OX1/2R antagonists, or Zolpidem. We also analyzed electroencephalogram (EEG) power spectra of wakefulness, rapid eye movement (REM) sleep, and non-REM (NREM) sleep following the injections of vehicle, OX1/2R antagonists, and Zolpidem in young adult mice.ResultsAcute optogenetic stimulation of Hcrt neurons at different frequencies resulted in wakefulness. Treatment with dual OX1/2R antagonists (DORAs) DORA12 and MK6096, as well as selective OX2R antagonist MK1064 and Zolpidem, but not selective OX1R antagonist 1SORA1, significantly reduced the bout length of optogenetic stimulation-evoked wakefulness episode. Fiber photometry recordings of GCaMP6f signals showed that Hcrt neurons are active during wakefulness, even in the presence of OXR antagonists. Treatment with dual OX1/2R antagonists improved memory function despite optogenetic sleep fragmentation caused impaired memory function in a NOR test.ConclusionsOur results show DORAs and selective OX2R antagonists stabilize sleep and improve sleep-dependent cognitive processes even when challenged by optogenetic stimulation mimicking highly arousing stimuli.

| S-EPMC6454482 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data