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Anthony L. Gotter - One of the best experts on this subject based on the ideXlab platform.
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Orexin signaling during social defeat stress influences subsequent social interaction behaviour and recognition memory.
Behavioural brain research, 2018Co-Authors: Darrell Eacret, John J Renger, Christopher J. Winrow, Anthony L. Gotter, Laura A. Grafe, Jane Dobkin, Seema BhatnagarAbstract:Abstract Orexins are neuropeptides synthesized in the lateral hypothalamus that influence arousal, feeding, reward pathways, and the response to stress. However, the role of Orexins in repeated stress is not fully characterized. Here, we examined how Orexins and their Receptors contribute to the coping response during repeated social defeat and subsequent anxiety-like and memory-related behaviors. Specifically, we used Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) to stimulate Orexins prior to each of five consecutive days of social defeat stress in adult male rats. Additionally, we determined the role of the Orexin 2 Receptor in these behaviors by using a selective Orexin 2 Receptor antagonist (MK-1064) administered prior to each social defeat. Following the 5 day social defeat conditioning period, rats were evaluated in social interaction and novel object recognition paradigms to assess anxiety-like behavior and recognition memory, respectively. Activation of Orexin neurons by DREADDs prior to each social defeat decreased the average latency to become defeated across 5 days, indicative of a passive coping strategy that we have previously linked to a stress vulnerable phenotype. Moreover, stimulation of Orexin signaling during defeat conditioning decreased subsequent social interaction and performance in the novel object recognition test indicating increased subsequent anxiety-like behavior and reduced recognition memory. Blocking the Orexin 2 Receptor during repeated defeat did not alter these effects. Together, our results suggest that Orexin neuron activation produces a passive coping phenotype during social defeat leading to subsequent anxiety-like behaviors and memory deficits.
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Orexin 2 Receptor regulation of the hypothalamic pituitary adrenal hpa response to acute and repeated stress
Neuroscience, 2017Co-Authors: Laura A. Grafe, John J Renger, Christopher J. Winrow, Anthony L. Gotter, Darrell Eacret, Seema Bhatnagar, Sandra LuzAbstract:Orexins are hypothalamic neuropeptides that have a documented role in mediating the acute stress response. However, their role in habituation to repeated stress, and the role of Orexin Receptors (OX1R and OX2R) in the stress response, has yet to be defined. Orexin neuronal activation and levels in the cerebrospinal fluid (CSF) were found to be stimulated with acute restraint, but were significantly reduced by day five of repeated restraint. As certain disease states such as panic disorder are associated with increased central Orexin levels and failure to habituate to repeated stress, the effect of activating Orexin signaling via Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) on the hypothalamic-pituitary-adrenal (HPA) response was evaluated after repeated restraint. While vehicle-treated rats displayed habituation of Adrenocorticotropic Hormone (ACTH) from day 1 to day 5 of restraint, stimulating Orexins did not further increase ACTH beyond vehicle levels for either acute or repeated restraint. We delineated the roles of Orexin Receptors in acute and repeated stress using a selective OX2R antagonist (MK-1064). Pretreatment with MK-1064 reduced day 1 ACTH levels, but did not allow further habituation on day 5 compared with vehicle-treated rats, indicating that endogenous OX2R activity plays a role in acute stress, but not in habituation to repeated stress. However, in restrained rats with further stimulated Orexins by DREADDs, MK-1064 decreased ACTH levels on day 5. Collectively, these results indicate that the OX2R plays a role in acute stress, and can prevent habituation to repeated stress under conditions of high Orexin release.
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Orexin 2 Receptor antagonism is sufficient to promote nrem and rem sleep from mouse to man
Scientific Reports, 2016Co-Authors: Anthony L. Gotter, Joanne Stevens, Pamela L Tannenbaum, Steven V. Fox, Anthony J Roecker, Mark Forman, Charles M Harrell, Vladimir Svetnik, Ka Lai Yee, Susan L GarsonAbstract:Orexin neuropeptides regulate sleep/wake through Orexin Receptors (OX1R, OX2R); OX2R is the predominant mediator of arousal promotion. The potential for single OX2R antagonism to effectively promote sleep has yet to be demonstrated in humans. MK-1064 is an OX2R-single antagonist. Preclinically, MK-1064 promotes sleep and increases both rapid eye movement (REM) and non-REM (NREM) sleep in rats at OX2R occupancies higher than the range observed for dual Orexin Receptor antagonists. Similar to dual antagonists, MK-1064 increases NREM and REM sleep in dogs without inducing cataplexy. Two Phase I studies in healthy human subjects evaluated safety, tolerability, pharmacokinetics and sleep-promoting effects of MK-1064, and demonstrated dose-dependent increases in subjective somnolence (via Karolinska Sleepiness Scale and Visual Analogue Scale measures) and sleep (via polysomnography), including increased REM and NREM sleep. Thus, selective OX2R antagonism is sufficient to promote REM and NREM sleep across species, similarly to that seen with dual Orexin Receptor antagonism.
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Pharmacological evaluation of Orexin Receptor antagonists in preclinical animal models of pain.
Journal of Neurogenetics, 2016Co-Authors: Terrence P Mcdonald, Christopher J. Winrow, Anthony L. Gotter, Paul J Coleman, Hongyu A. Liang, Raul Sanoja, Scott D. Kuduk, Karen M. Smith, John J RengerAbstract:Orexin signaling, known to modulate arousal and vigilance, is also involved in nociception as Orexin neurons project to regions of the brain and spinal cord involved in pain processing, and the administration of Orexin peptides can alter pain response in a wide range of preclinical models. Pharmacological treatment with the potent, selective and structurally distinct dual Orexin Receptor antagonists (ORAs) DORA-12 and DORA-2 significantly reduced pain responses during both phases I and II of the mouse formalin pain model and significantly reversed hyperalgesia in the rat complete Freund's adjuvant pain model, respectively. Significant antinociceptive effects of DORA-12 in the formalin model were also observed in Orexin 1 Receptor (OX1R) knockout mice, but not Orexin 2 Receptor (OX2R) or OX1R/OX2R double knockout mice. Mechanical hypersensitivity was significantly reduced with a series of structurally distinct, potent and highly selective ORAs (DORA-2, DORA-12 and DORA-22) in the rat spinal nerve ligation (SNL) injury model of neuropathic pain. Selective pharmacological targeting of OX2R with 2-SORA-7 also reduced pain responses in acute inflammatory (complete Freund's adjuvant) and neuropathic (SNL) rat pain models. Performance on the rotarod test of psychomotor performance and baseline thermal sensitivity were not affected in OX1R/OX2R knockout mice or ORA-treated mice, indicating that the observed pain-reducing effects were not due to sedation or motor deficits. These findings indicate that ORAs have pain-reducing effects across a number of acute and chronic neuropathic preclinical mouse and rat pain models. Further studies on the potential pain-relieving effects of Orexin Receptor antagonism are warranted.
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Discovery of piperidine ethers as selective Orexin Receptor antagonists (SORAs) inspired by filorexant.
Bioorganic & Medicinal Chemistry Letters, 2015Co-Authors: Izzat T. Raheem, Susan L Garson, Anthony L. Gotter, Michael J Breslin, Christopher D. Cox, Joseph G Bruno, Donghui Cui, Tamara D. Cabalu, Andrew J. Cooke, Steven V. FoxAbstract:Highly selective Orexin Receptor antagonists (SORAs) of the Orexin 2 Receptor (OX2R) have become attractive targets both as potential therapeutics for insomnia as well as biological tools to help further elucidate the underlying pharmacology of the Orexin signaling pathway. Herein, we describe the discovery of a novel piperidine ether 2-SORA class identified by systematic lead optimization beginning with filorexant, a dual Orexin Receptor antagonist (DORA) that recently completed Phase 2 clinical trials. Changes to the ether linkage and pendant heterocycle of filorexant were found to impart significant selectivity for OX2R, culminating in lead compound PE-6. PE-6 displays sub-nanomolar binding affinity and functional potency on OX2R while maintaining >1600-fold binding selectivity and >200-fold functional selectivity versus the Orexin 1 Receptor (OX1R). PE-6 bears a clean off-target profile, a good overall preclinical pharmacokinetic (PK) profile, and reduces wakefulness with increased NREM and REM sleep when evaluated in vivo in a rat sleep study. Importantly, subtle structural changes to the piperidine ether class impart dramatic changes in Receptor selectivity. To this end, our laboratories have identified multiple piperidine ether 2-SORAs, 1-SORAs, and DORAs, providing access to a number of important biological tool compounds from a single structural class.
Ling Ling Hwang - One of the best experts on this subject based on the ideXlab platform.
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role of the Orexin 2 Receptor in palatable food consumption associated cardiovascular reactivity in spontaneously hypertensive rats
Scientific Reports, 2018Co-Authors: Shang Cheng Huang, Yen Hsien Lee, Yu Wen E Dai, Yu Chun Chen, Ling Ling HwangAbstract:Hypertensive subjects often exhibit exaggerated cardiovascular reactivity. An overactive Orexin system underlies the pathophysiology of hypertension. We examined Orexin’s roles in eating-associated cardiovascular reactivity in spontaneously hypertensive rats (SHRs) and Wistar-Kyoto (WKY) rats. Results showed eating regular chow or palatable food (sucrose agar) was accompanied by elevated arterial pressure and heart rate. In both SHRs and WKY rats, the cardiovascular responses associated with sucrose-agar consumption were greater than that with regular-chow consumption. Additionally, SHRs exhibited greater cardiovascular responses than WKY rats did to regular-chow and palatable food consumption. Central Orexin 2 Receptor (OX2R) blockade attenuated sucrose-agar consumption-associated cardiovascular response only in SHRs. In both SHRs and WKY rats, OX2R blockade did not affect regular-chow consumption-associated cardiovascular responses. Greater numbers of c-Fos-positive cells in the rostral ventrolateral medulla (RVLM) and of c-Fos-positive Orexin neurons in the dorsomedial hypothalamus (DMH) were detected in sucrose agar-treated SHRs, compared to regular chow-treated SHRs and to sucrose agar-treated WKY rats. Central OX2R blockade reduced the number of c-Fos-positive cells in the RVLM only in sucrose agar-treated SHRs. We concluded that in SHRs, Orexin neurons in the DMH might be overactive during eating palatable food and may further elicit exaggerated cardiovascular responses via an OX2R-RVLM pathway.
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spontaneously hypertensive rats have more Orexin neurons in the hypothalamus and enhanced Orexinergic input and Orexin 2 Receptor associated nitric oxide signalling in the rostral ventrolateral medulla
Experimental Physiology, 2015Co-Authors: Yen Hsien Lee, Shang Cheng Huang, Yu Wen E Dai, Min Chien Tsai, Ling Ling HwangAbstract:New Findings What is the central question of this study? Our previous study demonstrates that elevated Orexin 2 Receptor (OX2R) activity within the rostral ventrolateral medulla (RVLM) contributes to hypertension in spontaneously hypertensive rats (SHRs), and a lower OX2R protein level was detected in their RVLM. The present study aims to explore the mechanisms underlying elevated Orexinergic activity in the RVLM of SHRs, compared with their normotensive counterparts, Wistar-Kyoto rats. What is the main finding and its importance? Increased Orexinergic input into the RVLM and enhanced OX2R responsiveness in the RVLM, which was mainly mediated by augmented OX2R–neuronal nitric oxide synthase signalling, may underlie the elevated OX2R activity within the RVLM of SHRs. Abstract Our previous study showed that elevated Orexin 2 Receptor (OX2R) activity within the rostral ventrolateral medulla (RVLM) contributes to hypertension in spontaneously hypertensive rats (SHRs). Herein, we investigated the mechanism(s) underlying the elevated OX2R activity. The following results were found. (i) More hypothalamic Orexin A-immunoreactive (OXA-IR) cells existed in SHRs than in Wistar-Kyoto (WKY) rats at either 4 (2217 ± 43 versus 1809 ± 69) or 16 weeks of age (1829 ± 59 versus 1230 ± 84). The number of OXA-IR cells that project to the RVLM was higher in 16-week-old SHRs than in WKY rats (91 ± 11 versus 52 ± 11). (ii) Higher numbers of OXA-IR and RVLM-projecting OXA-IR cells were found in the dorsomedial and perifornical hypothalamus of 16-week-old SHRs. (iii) Spontaneously hypertensive rats had higher levels of Orexin A and B in the hypothalamus and higher levels of Orexin A in the RVLM than did WKY rats. (iv) Unilateral intra-RVLM application of OX2R agonist, Orexin A or [Ala11,d-Leu15]-Orexin B (50 pmol) induced a larger pressor response in SHRs than in WKY rats. (v) Intra-RVLM pretreatment with a neuronal nitric oxide synthase (NOS) inhibitor, 7-nitro-indazole (2.5 pmol), or a soluble guanylate cyclase inhibitor, methylene blue (250 pmol), reducedthe intra-RVLM [Ala11,d-Leu15]-Orexin B-induced pressor response in both WKY rats and SHRs. In contrast, an inducible NOS inhibitor, aminoguanidine (100 pmol), was ineffective. (vi) Neuronal NOS was co-expressed with OX2R in RVLM neurons. In conclusion, increased Orexinergic input and enhanced OX2R–neuronal NOS signalling may underlie elevated OX2R activity in the RVLM and contribute to the pathophysiology of hypertension in SHRs.
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Orexins depolarize rostral ventrolateral medulla neurons and increase arterial pressure and heart rate in rats mainly via Orexin 2 Receptors
Journal of Pharmacology and Experimental Therapeutics, 2010Co-Authors: Shang Cheng Huang, Yen Hsien Lee, Yu Wen E Dai, Lihchu Chiou, Ling Ling HwangAbstract:An injection of Orexin A or B into the cisterna magna or the rostral ventrolateral medulla (RVLM), where bulbospinal vasomotor neurons are located, elevated arterial pressure (AP) and heart rate (HR). We examined how Orexins affected RVLM neurons to regulate cardiovascular functions by using in vitro recordings of neuronal activity of the RVLM and in vivo measurement of cardiovascular functions in rats. Orexin A and B concentration-dependently depolarized RVLM neurons. At 100 nM, both peptides excited 42% of RVLM neurons. Tetrodotoxin failed to block Orexin-induced depolarization. In the presence of N-(2-methyl-6-benzoxazolyl)-N'-1, 5-naphthyridin-4-yl urea (SB-334867), an Orexin 1 Receptor (OX(1)R) antagonist, Orexin A depolarized 42% of RVLM neurons with a smaller, but not significantly different, amplitude (4.9 +/- 0.8 versus 7.2 +/- 1.1 mV). In the presence of (2S)-1- (3,4-dihydro-6,7-dimethoxy-2(1H)-isoquinolinyl)-3,3-dimethyl-2-[(4-pyridinylmethyl)amino]-1-butanone hydrochloride (TCS OX2 29), an Orexin 2 Receptor (OX(2)R) antagonist, Orexin A depolarized 25% of RVLM neurons with a significantly smaller amplitude (1.7 +/- 0.5 mV). Coapplication of both antagonists completely eliminated Orexin A-induced depolarization. An OX(2)R agonist, [Ala(11),D-Leu(15)]-Orexin B, concentration-dependently depolarized RVLM neurons. Regarding neuronal phenotypes, Orexins depolarized 88% of adrenergic, 43% of nonadrenergic, and 36 to 41% of rhythmically firing RVLM neurons. Intracisternal TCS OX2 29 (3 and 10 nmol) suppressed intracisternal Orexin A-induced increases of AP and HR, whereas intracisternal SB-334867 (3 and 10 nmol) had no effect on the Orexin A-induced increase of HR but suppressed the Orexin A-induced pressor response at 10 nmol. We concluded that Orexins directly excite RVLM neurons, which include bulbospinal vasomotor neurons, and regulate cardiovascular function mainly via the OX(2)R, with a smaller contribution from the OX(1)R.
Susan L Garson - One of the best experts on this subject based on the ideXlab platform.
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Orexin 2 Receptor antagonism is sufficient to promote nrem and rem sleep from mouse to man
Scientific Reports, 2016Co-Authors: Anthony L. Gotter, Joanne Stevens, Pamela L Tannenbaum, Steven V. Fox, Anthony J Roecker, Mark Forman, Charles M Harrell, Vladimir Svetnik, Ka Lai Yee, Susan L GarsonAbstract:Orexin neuropeptides regulate sleep/wake through Orexin Receptors (OX1R, OX2R); OX2R is the predominant mediator of arousal promotion. The potential for single OX2R antagonism to effectively promote sleep has yet to be demonstrated in humans. MK-1064 is an OX2R-single antagonist. Preclinically, MK-1064 promotes sleep and increases both rapid eye movement (REM) and non-REM (NREM) sleep in rats at OX2R occupancies higher than the range observed for dual Orexin Receptor antagonists. Similar to dual antagonists, MK-1064 increases NREM and REM sleep in dogs without inducing cataplexy. Two Phase I studies in healthy human subjects evaluated safety, tolerability, pharmacokinetics and sleep-promoting effects of MK-1064, and demonstrated dose-dependent increases in subjective somnolence (via Karolinska Sleepiness Scale and Visual Analogue Scale measures) and sleep (via polysomnography), including increased REM and NREM sleep. Thus, selective OX2R antagonism is sufficient to promote REM and NREM sleep across species, similarly to that seen with dual Orexin Receptor antagonism.
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Discovery of piperidine ethers as selective Orexin Receptor antagonists (SORAs) inspired by filorexant.
Bioorganic & Medicinal Chemistry Letters, 2015Co-Authors: Izzat T. Raheem, Susan L Garson, Anthony L. Gotter, Michael J Breslin, Christopher D. Cox, Joseph G Bruno, Donghui Cui, Tamara D. Cabalu, Andrew J. Cooke, Steven V. FoxAbstract:Highly selective Orexin Receptor antagonists (SORAs) of the Orexin 2 Receptor (OX2R) have become attractive targets both as potential therapeutics for insomnia as well as biological tools to help further elucidate the underlying pharmacology of the Orexin signaling pathway. Herein, we describe the discovery of a novel piperidine ether 2-SORA class identified by systematic lead optimization beginning with filorexant, a dual Orexin Receptor antagonist (DORA) that recently completed Phase 2 clinical trials. Changes to the ether linkage and pendant heterocycle of filorexant were found to impart significant selectivity for OX2R, culminating in lead compound PE-6. PE-6 displays sub-nanomolar binding affinity and functional potency on OX2R while maintaining >1600-fold binding selectivity and >200-fold functional selectivity versus the Orexin 1 Receptor (OX1R). PE-6 bears a clean off-target profile, a good overall preclinical pharmacokinetic (PK) profile, and reduces wakefulness with increased NREM and REM sleep when evaluated in vivo in a rat sleep study. Importantly, subtle structural changes to the piperidine ether class impart dramatic changes in Receptor selectivity. To this end, our laboratories have identified multiple piperidine ether 2-SORAs, 1-SORAs, and DORAs, providing access to a number of important biological tool compounds from a single structural class.
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discovery of 5 chloro n 5 6 dimethoxypyridin 2 yl methyl 2 2 5 3 terpyridine 3 carboxamide mk 1064 a selective Orexin 2 Receptor antagonist 2 sora for the treatment of insomnia
ChemMedChem, 2014Co-Authors: Anthony J Roecker, Susan L Garson, John D. Schreier, Wei Lemaire, Swati P Mercer, Meacham C Harrell, Joseph G Bruno, Mark E Fraley, Justin T Steen, Anthony L. GotterAbstract:The field of small-molecule Orexin antagonist research has evolved rapidly in the last 15 years from the discovery of the Orexin peptides to clinical proof-of-concept for the treatment of insomnia. Clinical programs have focused on the development of antagonists that reversibly block the action of endogenous peptides at both the Orexin 1 and Orexin 2 Receptors (OX1 R and OX2 R), termed dual Orexin Receptor antagonists (DORAs), affording late-stage development candidates including Merck's suvorexant (new drug application filed 2012). Full characterization of the pharmacology associated with antagonism of either OX1 R or OX2 R alone has been hampered by the dearth of suitable subtype-selective, orally bioavailable ligands. Herein, we report the development of a selective Orexin 2 antagonist (2-SORA) series to afford a potent, orally bioavailable 2-SORA ligand. Several challenging medicinal chemistry issues were identified and overcome during the development of these 2,5-disubstituted nicotinamides, including reversible CYP inhibition, physiochemical properties, P-glycoprotein efflux and bioactivation. This article highlights structural modifications the team utilized to drive compound design, as well as in vivo characterization of our 2-SORA clinical candidate, 5''-chloro-N-[(5,6-dimethoxypyridin-2-yl)methyl]-2,2':5',3''-terpyridine-3'-carboxamide (MK-1064), in mouse, rat, dog, and rhesus sleep models.
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discovery of 2 5 diarylnicotinamides as selective Orexin 2 Receptor antagonists 2 soras
Bioorganic & Medicinal Chemistry Letters, 2013Co-Authors: Swati P Mercer, Susan L Garson, Wei Lemaire, Rodney A. Bednar, Duane R Reiss, Anthony J Roecker, Meacham C Harrell, Kathy L Murphy, Joseph G Bruno, Donghui CuiAbstract:The Orexin (or hypocretin) system has been identified as a novel target for the treatment of insomnia due to the wealth of biological and genetic data discovered over the past decade. Recently, clinical proof-of-concept was achieved for the treatment of primary insomnia using dual (OX1R/OX2R) Orexin Receptor antagonists. However, elucidation of the pharmacology associated with selective Orexin-2 Receptor antagonists (2-SORAs) has been hampered by the lack of orally bioavailable, highly selective small molecule probes. Herein, the discovery and optimization of a novel series of 2,5-diarylnicotinamides as potent and orally bioavailable Orexin-2 Receptor selective antagonists is described. A compound from this series demonstrated potent sleep promotion when dosed orally to EEG telemetrized rats.
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Quantitative Electroencephalography Within Sleep/Wake States Differentiates GABA_A Modulators Eszopiclone and Zolpidem From Dual Orexin Receptor Antagonists in Rats
Neuropsychopharmacology, 2013Co-Authors: Steven V. Fox, Susan L Garson, Anthony L. Gotter, Jason M Uslaner, Alan T Savitz, Pamela L Tannenbaum, Spencer J Tye, Joseph I Brunner, Terrence P Mcdonald, Robert HodgsonAbstract:Dual Orexin Receptor antagonists (DORAs) induce sleep by blocking Orexin 1 and Orexin 2 Receptor-mediated activities responsible for regulating wakefulness. DORAs represent a potential alternative mechanism to the current standard of care that includes the γ -aminobutyric acid (GABA)_A Receptor-positive allosteric modulators, eszopiclone and zolpidem. This work uses an innovative method to analyze electroencephalogram (EEG) spectral frequencies within sleep/wake states to differentiate the effects of GABA_A modulators from DORA-22, an analog of the DORA MK-6096, in Sprague–Dawley rats. The effects of low, intermediate, and high doses of eszopiclone, zolpidem, and DORA-22 were examined after first defining each compound’s ability to promote sleep during active-phase dosing. The EEG spectral frequency power within specific sleep stages was calculated in 1-Hz intervals from 1 to 100 Hz within each sleep/wake state for the first 4 h after the dose. Eszopiclone and zolpidem produced marked, dose-responsive disruptions in sleep stage-specific EEG spectral profiles compared with vehicle treatment. In marked contrast, DORA-22 exhibited marginal changes in the spectral profile, observed only during rapid eye movement sleep, and only at the highest dose tested. Moreover, while eszopiclone- and zolpidem-induced changes were evident in the inactive period, the EEG spectral responses to DORA-22 were absent during this phase. These results suggest that DORA-22 differs from eszopiclone and zolpidem whereby DORA-22 promotes somnolence without altering the neuronal network EEG activity observed during normal sleep.
Seema Bhatnagar - One of the best experts on this subject based on the ideXlab platform.
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Orexin signaling during social defeat stress influences subsequent social interaction behaviour and recognition memory.
Behavioural brain research, 2018Co-Authors: Darrell Eacret, John J Renger, Christopher J. Winrow, Anthony L. Gotter, Laura A. Grafe, Jane Dobkin, Seema BhatnagarAbstract:Abstract Orexins are neuropeptides synthesized in the lateral hypothalamus that influence arousal, feeding, reward pathways, and the response to stress. However, the role of Orexins in repeated stress is not fully characterized. Here, we examined how Orexins and their Receptors contribute to the coping response during repeated social defeat and subsequent anxiety-like and memory-related behaviors. Specifically, we used Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) to stimulate Orexins prior to each of five consecutive days of social defeat stress in adult male rats. Additionally, we determined the role of the Orexin 2 Receptor in these behaviors by using a selective Orexin 2 Receptor antagonist (MK-1064) administered prior to each social defeat. Following the 5 day social defeat conditioning period, rats were evaluated in social interaction and novel object recognition paradigms to assess anxiety-like behavior and recognition memory, respectively. Activation of Orexin neurons by DREADDs prior to each social defeat decreased the average latency to become defeated across 5 days, indicative of a passive coping strategy that we have previously linked to a stress vulnerable phenotype. Moreover, stimulation of Orexin signaling during defeat conditioning decreased subsequent social interaction and performance in the novel object recognition test indicating increased subsequent anxiety-like behavior and reduced recognition memory. Blocking the Orexin 2 Receptor during repeated defeat did not alter these effects. Together, our results suggest that Orexin neuron activation produces a passive coping phenotype during social defeat leading to subsequent anxiety-like behaviors and memory deficits.
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Orexin 2 Receptor regulation of the hypothalamic pituitary adrenal hpa response to acute and repeated stress
Neuroscience, 2017Co-Authors: Laura A. Grafe, John J Renger, Christopher J. Winrow, Anthony L. Gotter, Darrell Eacret, Seema Bhatnagar, Sandra LuzAbstract:Orexins are hypothalamic neuropeptides that have a documented role in mediating the acute stress response. However, their role in habituation to repeated stress, and the role of Orexin Receptors (OX1R and OX2R) in the stress response, has yet to be defined. Orexin neuronal activation and levels in the cerebrospinal fluid (CSF) were found to be stimulated with acute restraint, but were significantly reduced by day five of repeated restraint. As certain disease states such as panic disorder are associated with increased central Orexin levels and failure to habituate to repeated stress, the effect of activating Orexin signaling via Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) on the hypothalamic-pituitary-adrenal (HPA) response was evaluated after repeated restraint. While vehicle-treated rats displayed habituation of Adrenocorticotropic Hormone (ACTH) from day 1 to day 5 of restraint, stimulating Orexins did not further increase ACTH beyond vehicle levels for either acute or repeated restraint. We delineated the roles of Orexin Receptors in acute and repeated stress using a selective OX2R antagonist (MK-1064). Pretreatment with MK-1064 reduced day 1 ACTH levels, but did not allow further habituation on day 5 compared with vehicle-treated rats, indicating that endogenous OX2R activity plays a role in acute stress, but not in habituation to repeated stress. However, in restrained rats with further stimulated Orexins by DREADDs, MK-1064 decreased ACTH levels on day 5. Collectively, these results indicate that the OX2R plays a role in acute stress, and can prevent habituation to repeated stress under conditions of high Orexin release.
Anthony J Roecker - One of the best experts on this subject based on the ideXlab platform.
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Orexin 2 Receptor antagonism is sufficient to promote nrem and rem sleep from mouse to man
Scientific Reports, 2016Co-Authors: Anthony L. Gotter, Joanne Stevens, Pamela L Tannenbaum, Steven V. Fox, Anthony J Roecker, Mark Forman, Charles M Harrell, Vladimir Svetnik, Ka Lai Yee, Susan L GarsonAbstract:Orexin neuropeptides regulate sleep/wake through Orexin Receptors (OX1R, OX2R); OX2R is the predominant mediator of arousal promotion. The potential for single OX2R antagonism to effectively promote sleep has yet to be demonstrated in humans. MK-1064 is an OX2R-single antagonist. Preclinically, MK-1064 promotes sleep and increases both rapid eye movement (REM) and non-REM (NREM) sleep in rats at OX2R occupancies higher than the range observed for dual Orexin Receptor antagonists. Similar to dual antagonists, MK-1064 increases NREM and REM sleep in dogs without inducing cataplexy. Two Phase I studies in healthy human subjects evaluated safety, tolerability, pharmacokinetics and sleep-promoting effects of MK-1064, and demonstrated dose-dependent increases in subjective somnolence (via Karolinska Sleepiness Scale and Visual Analogue Scale measures) and sleep (via polysomnography), including increased REM and NREM sleep. Thus, selective OX2R antagonism is sufficient to promote REM and NREM sleep across species, similarly to that seen with dual Orexin Receptor antagonism.
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discovery of mk 3697 a selective Orexin 2 Receptor antagonist 2 sora for the treatment of insomnia
Bioorganic & Medicinal Chemistry Letters, 2014Co-Authors: Anthony J Roecker, John D. Schreier, Wei Lemaire, Christopher D. Cox, Swati P Mercer, Thomas S Reger, Christa M Mattern, Jeffrey M Bergman, Rowena V Cube, Joseph G BrunoAbstract:Orexin Receptor antagonists have demonstrated clinical utility for the treatment of insomnia. The majority of clinical efforts to date have focused on the development of dual Orexin Receptor antagonists (DORAs), small molecules that antagonize both the Orexin 1 and Orexin 2 Receptors. Our group has recently disclosed medicinal chemistry efforts to identify highly potent, orally bioavailable selective Orexin 2 Receptor antagonists (2-SORAs) that possess acceptable profiles for clinical development. Herein we report additional SAR studies within the ‘triaryl’ amide 2-SORA series focused on improvements in compound stability in acidic media and time-dependent inhibition of CYP3A4. These studies resulted in the discovery of 2,5-disubstituted isonicotinamide 2-SORAs such as compound 24 that demonstrated improved stability and TDI profiles as well as excellent sleep efficacy across species.
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selective Orexin 2 Receptor antagonism blocks cue induced reinstatement but not nicotine self administration or nicotine induced reinstatement
Behavioural Brain Research, 2014Co-Authors: Jason M Uslaner, Christopher J. Winrow, Anthony L. Gotter, Paul J Coleman, Anthony J Roecker, Pete H Hutson, John J RengerAbstract:The Orexinergic system has been implicated in a number of behaviors, including reward and incentive motivation. Orexin 1 Receptor antagonism has been reported to reduce drug self-administration, conditioned place preference, and reinstatement in rodents, but the role of the Orexin 2 Receptor is unclear. Here we evaluated the impact of the novel and selective Orexin 2 Receptor antagonist, 2-SORA 18, on motivation for nicotine as measured by responding on a progressive ratio schedule, as well as cue-induced reinstatement of a response previously associated with nicotine reward, and nicotine-induced reinstatement. 2-SORA 18 demonstrated selective effects on these behaviors. Specifically, doses up to 60 mg/kg 2-SORA 18 were without significant effect on nicotine self-administration or nicotine-induced reinstatement, but doses as low as 15 mg/kg 2-SORA 18 completely blocked cue-induced reinstatement. These findings indicate that Orexin 2 Receptor antagonism might have utility for attenuating relapse, particularly for patients sensitive to environmental stimuli associated with drug taking.
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discovery of 5 chloro n 5 6 dimethoxypyridin 2 yl methyl 2 2 5 3 terpyridine 3 carboxamide mk 1064 a selective Orexin 2 Receptor antagonist 2 sora for the treatment of insomnia
ChemInform, 2014Co-Authors: Anthony J RoeckerAbstract:The development of title compound (I), one of the most potent and selective Orexin 2 antagonists (2-SORA) reported to date, is described including SAR study.
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discovery of 5 chloro n 5 6 dimethoxypyridin 2 yl methyl 2 2 5 3 terpyridine 3 carboxamide mk 1064 a selective Orexin 2 Receptor antagonist 2 sora for the treatment of insomnia
ChemMedChem, 2014Co-Authors: Anthony J Roecker, Susan L Garson, John D. Schreier, Wei Lemaire, Swati P Mercer, Meacham C Harrell, Joseph G Bruno, Mark E Fraley, Justin T Steen, Anthony L. GotterAbstract:The field of small-molecule Orexin antagonist research has evolved rapidly in the last 15 years from the discovery of the Orexin peptides to clinical proof-of-concept for the treatment of insomnia. Clinical programs have focused on the development of antagonists that reversibly block the action of endogenous peptides at both the Orexin 1 and Orexin 2 Receptors (OX1 R and OX2 R), termed dual Orexin Receptor antagonists (DORAs), affording late-stage development candidates including Merck's suvorexant (new drug application filed 2012). Full characterization of the pharmacology associated with antagonism of either OX1 R or OX2 R alone has been hampered by the dearth of suitable subtype-selective, orally bioavailable ligands. Herein, we report the development of a selective Orexin 2 antagonist (2-SORA) series to afford a potent, orally bioavailable 2-SORA ligand. Several challenging medicinal chemistry issues were identified and overcome during the development of these 2,5-disubstituted nicotinamides, including reversible CYP inhibition, physiochemical properties, P-glycoprotein efflux and bioactivation. This article highlights structural modifications the team utilized to drive compound design, as well as in vivo characterization of our 2-SORA clinical candidate, 5''-chloro-N-[(5,6-dimethoxypyridin-2-yl)methyl]-2,2':5',3''-terpyridine-3'-carboxamide (MK-1064), in mouse, rat, dog, and rhesus sleep models.