1,3-Biarylureas as selective non-peptide antagonists of the orexin-1 receptor

Porter, Roderick A.; Chan, Wai N.; Coulton, Steven; Johns, Amanda; Hadley, Michael S.; Widdowson, Katherine L.; Jerman, Jeffrey C.; Brough, Stephen; Coldwell, Martyn C.; Smart, Darren; Jewitt, A. Frances; Jeffrey, Philip D.; Austin, Nigel

doi:10.1016/s0960-894x(01)00343-2

Cited by 148 publications

(88 citation statements)

References 15 publications

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“…This is in line with a previous report on AR42J cells (19). Further pharmacological studies using the few currently available tools for orexin receptors also argue for a specific role of OX 2 R in AR42J cells because the proapoptotic effect of orexin can be mimicked by the specific OX 2 R agonist [Ala 11, d-Leu 15 ]orexin-B (21) but cannot be reversed by the OX 1 R antagonists SB 33487 (22,23) or SB 408124 (24). The dose responses of orexin-A and orexin-B for inhibiting cell growth and promoting cell death are superimposable in both CHO/OX 2 R and AR42J cells.…”

Section: Discussionsupporting

confidence: 89%

Orexin-Induced Apoptosis: The Key Role of the Seven-Transmembrane Domain Orexin Type 2 Receptor

et al. 2006

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3). Orexins were initially characterized in hypothalamic neurons, which project to and excite many brain areas (4, 5). Orexin neurons have functional interactions with hypothalamic feeding pathways and monoaminergic-cholinergic centers to provide a link between energy balance and the brain mechanisms that coordinate sleep/wakefulness states and motivated behavior such as food seeking (6 -10). In this context, the characterization of orexin deficiency in narcoleptic patients (11) and mutation of orexin receptors in canine (12) and murine (13) narcolepsy emphasized the key role of orexins in the regulation of sleep/wakefulness. More recent studies showed that orexins are not restricted to the hypothalamus but are also expressed in peripheral tissues including adrenals, gastrointestinal tract, or endocrine pancreas (for review see Ref.3). Orexins alter endocrine function (14) by increasing glucagon secretion and decreasing glucose-stimulated insulin release from pancreatic islets (15), suppressing GH secretion (16), or regulating corticotropin release (14).Two orexin receptor subtypes OX 1 R and OX 2 R have been cloned (1, 2). They are serpentine G protein-coupled receptors that bind both orexins with poor selectivity and appear to be coupled to calcium mobilization (1). In humans, OX 1 R and OX 2 R show 64% amino acid identity more particularly present in transmembrane domains whereas the N-terminal extracellular domain and C-terminal tail exhibit very weak sequence identity (3). Orexin receptors have been described in the central nervous system as well as peripheral organs (3,17).Recently we discovered a new unexpected aspect of orexins as potent proapoptotic peptides (18). We showed that orexin-A and orexin-B induce a drastic apoptosis in human colon cancer cell lines in culture resulting in massive reduction of cell growth. The effect was extended to human neuroblastoma cells (18). The OX 1 R but not the OX 2 R is expressed in colon cancer and neuroblastoma cells and was shown to be responsible for the proapoptotic effect of orexins. The role of OX 1 R in mediating apoptosis was further demonstrated by transfecting CHO cells with OX 1 R cDNA, which conferred the ability of orexins to promote apoptosis (18). The OX 1 R-mediated apoptosis has been shown to be associated with cytochrome c release into cytosol and activation of caspase-3 and caspase-7 (18).As mentioned above a second orexin receptor OX 2 R has been cloned (1). Like the OX 1 R, it is expressed in both the central nervous system and peripheral organs (3,17). However, its role in orexin-induced apoptosis is still unknown. In the present paper, we explored the role of OX 2 R with respect to apoptosis. We show that transfection of OX 2 R cDNA in

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Section: Discussionsupporting

confidence: 89%

Orexin-Induced Apoptosis: The Key Role of the Seven-Transmembrane Domain Orexin Type 2 Receptor

et al. 2006

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“…Both the orexin peptides and orexin receptors are widely distributed throughout the entire brain, including brain regions involved in drug reward and addiction, with somewhat different patterns of expression (Sakurai, 2003). 1-(2-Methylbenzoxazol-6-yl)-3- [1,5]naphthyridin-4-yl urea (SB-334867) is a selective antagonist of OX1R (Porter et al, 2001). Blockade of orexin signaling at OX1R via SB-334867 has been shown to significantly reduce cocaine self-administration under both a fixed ratio (FR) 5 schedule of reinforcement (J.…”

Section: Introductionmentioning

confidence: 99%

Orexin-1 Receptor Mediation of Cocaine Seeking in Male and Female Rats

Zhou¹,

Ghee²,

Chan³

et al. 2011

J Pharmacol Exp Ther

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Previous studies have shown that female rats exhibit enhanced cocaine seeking during multiple phases of cocaine addiction compared with males. The orexin/hypocretin system recently has been implicated in drug addiction in male rats. Based on the known sex differences in cocaine addiction, in the current study we examined orexin-mediated cocaine seeking during self-administration, extinction, and reinstatement in agematched male (initial weight 250 -300 g) and female (initial weight 175-225 g) Sprague-Dawley rats by using the orexin-1 receptor (OX1R) antagonist 1-(2-methylbenzoxazol-6-yl)-3-[1,5]naphthyridin-4-yl urea (SB-334867) (10 -30 mg/kg). OX1R blockade had no effect on established cocaine self-administration, but attenuated cocaine seeking during extinction in both male and female rats. It is noteworthy that OX1R blockade potently attenuated cue-induced reinstatement in males but had no effect on females. SB-334867 also reduced cocaine seeking during pharmacological stress-induced (yohimbine, 2.5 mg/kg) and yohimbine ϩ cue-induced reinstatement in both sexes. SB-334867 failed to affect reinstatement induced by cocaine (10 mg/kg) in either male or female rats, but selectively reduced cocaine ϩ cue-induced reinstatement only in males. In separate experiments examining basal and cocaine-induced locomotion, SB-334867 attenuated locomotion in both male and female rats. Finally, assessment of plasma and brain levels of SB-334867 showed that estrus females had slightly higher plasma levels than diestrus females, but no overall sex differences or estrous cycle differences were observed in plasma or brain SB-334867 concentrations. These results show that OX1R signaling plays a role in mediating cocaine seeking, but differs between the sexes for cue-induced reinstatement.

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“…1 h prior) in 1% (w/v) (2-hyroxypropyl)-b-cyclodextrin/10% dimethyl sulfoxide (DMSO) in sterile water (termed DMSO-vehicle; 1 h prior) were administered for extinction sessions 1-5. SB-334867 has been found to reach peak plasma and brain concentrations at 30 min post injection and maintains good exposure for up to 4 h (Porter et al, 2001). The dose of 5 mg/ kg yohimbine was selected based on previous reports that this dose increases plasma corticosterone levels (Banihashemi and Rinaman, 2006).…”

Section: Mouse Drug Treatmentmentioning

confidence: 99%

Yohimbine Depresses Excitatory Transmission in BNST and Impairs Extinction of Cocaine Place Preference Through Orexin-Dependent, Norepinephrine-Independent Processes

Conrad

Davis

Silberman

et al. 2012

Neuropsychopharmacol

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The alpha2 adrenergic receptor (a 2 -AR) antagonist yohimbine is a widely used tool for the study of anxiogenesis and stress-induced drug-seeking behavior. We previously demonstrated that yohimbine paradoxically depresses excitatory transmission in the bed nucleus of the stria terminalis (BNST), a region critical to the integration of stress and reward pathways, and produces an impairment of extinction of cocaine-conditioned place preference (cocaine-CPP) independent of a 2 -AR signaling. Recent studies show yohimbineinduced drug-seeking behavior is attenuated by orexin receptor 1 (OX 1 R) antagonists. Moreover, yohimbine-induced cocaine-seeking behavior is BNST-dependent. Here, we investigated yohimbine-orexin interactions. Our results demonstrate yohimbine-induced depression of excitatory transmission in the BNST is unaffected by alpha1-AR and corticotropin-releasing factor receptor-1 (CRFR 1 ) antagonists, but is (1) blocked by OxR antagonists and (2) absent in brain slices from orexin knockout mice. Although the actions of yohimbine were not mimicked by the norepinephrine transporter blocker reboxetine, they were by exogenously applied orexin A. We find that, as with yohimbine, orexin A depression of excitatory transmission in BNST is OX 1 R-dependent. Finally, we find these ex vivo effects are paralleled in vivo, as yohimbine-induced impairment of cocaine-CPP extinction is blocked by a systemically administered OX 1 R antagonist. These data highlight a new mechanism for orexin on excitatory anxiety circuits and demonstrate that some of the actions of yohimbine may be directly dependent upon orexin signaling and independent of norepinephrine and CRF in the BNST.

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1,3-Biarylureas as selective non-peptide antagonists of the orexin-1 receptor

Cited by 148 publications

References 15 publications

Orexin-Induced Apoptosis: The Key Role of the Seven-Transmembrane Domain Orexin Type 2 Receptor

Orexin-Induced Apoptosis: The Key Role of the Seven-Transmembrane Domain Orexin Type 2 Receptor

Orexin-1 Receptor Mediation of Cocaine Seeking in Male and Female Rats

Yohimbine Depresses Excitatory Transmission in BNST and Impairs Extinction of Cocaine Place Preference Through Orexin-Dependent, Norepinephrine-Independent Processes

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