RESUMEN

Dual orexin receptor antagonists (DORAs) are approved for the treatment of sleep onset and/or sleep maintenance insomnia. In the present disclosure, we report the discovery of a new class of DORAs designed to treat sleep disorders requiring a fast onset and a short duration of action (<4 h). We used early human pharmacokinetic-pharmacodynamic (PK-PD) predictions and in vivo experiments to identify DORAs eliciting this specific hypnotic profile. A high-throughput screening campaign revealed hits based on a rarely precedented tricyclic pyrazolidine scaffold. After unsuccessful structure-activity-relationship (SAR) studies on this hit series, a scaffold hopping exercise, aimed at reducing the molecular complexity of the tricyclic scaffold, resulted in the discovery of the 2-acyl-1-biarylmethylpyrazolidine series. SAR studies on this achiral series gave rise to the lead compound DORA 42. In vitro and in vivo parameters of DORA 42, and its PK-PD simulation for human use are detailed.

Asunto(s)

Descubrimiento de Drogas , Antagonistas de los Receptores de Orexina , Pirazoles , Relación Estructura-Actividad , Humanos , Antagonistas de los Receptores de Orexina/farmacología , Antagonistas de los Receptores de Orexina/química , Antagonistas de los Receptores de Orexina/síntesis química , Pirazoles/química , Pirazoles/farmacología , Pirazoles/síntesis química , Animales , Estructura Molecular , Hipnóticos y Sedantes/farmacología , Hipnóticos y Sedantes/síntesis química , Hipnóticos y Sedantes/química , Hipnóticos y Sedantes/farmacocinética , Receptores de Orexina/metabolismo , Ratas , Relación Dosis-Respuesta a Droga , Masculino

RESUMEN

The neuromodulator orexin has been identified as a key factor for motivated arousal including recent evidence that sleep deprivation-induced enhancement of reward behavior is modulated by orexin. While orexin is not necessary for either reward or arousal behavior, orexin neurons' broad projections, ability to sense the internal state of the animal, and high plasticity of signaling in response to natural rewards and drugs of abuse may underlie heightened drug seeking, particularly in a subset of highly motivated reward seekers. As such, orexin receptor antagonists have gained deserved attention for putative use in addiction treatments. Ongoing and future clinical trials are expected to identify individuals most likely to benefit from orexin receptor antagonist treatment to promote abstinence, such as those with concurrent sleep disorders or high craving, while attention to methodological considerations will aid interpretation of the numerous preclinical studies investigating disparate aspects of the role of orexin in reward and arousal.

Asunto(s)

Nivel de Alerta , Neuropéptidos , Receptores de Orexina , Orexinas , Recompensa , Orexinas/metabolismo , Humanos , Animales , Nivel de Alerta/fisiología , Neuropéptidos/metabolismo , Receptores de Orexina/metabolismo , Antagonistas de los Receptores de Orexina/farmacología , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Motivación/fisiología , Neuronas/metabolismo

RESUMEN

Studies have indicated that stress-related symptoms can lead to hormonal and neural changes, affecting the pain threshold and nociceptive behaviors. The precise role of orexin receptors (OX1r and OX2r) in stress-induced analgesia (SIA) remains an inquiry yet to be comprehensively elucidated. The current investigation aimed to assess the impact of acute immobilization restraint stress on pain-related behavioral responses after administering antagonists targeting OX1r and OX2r in a rat model using the tail-flick test. After a period of five to seven days post-stereotaxic surgery in CA1, the baseline tail-flick latency (TFL) was recorded for each animal. Subsequently, rats were unilaterally administered varying doses of the OX1r antagonist (SB334867; 1, 3, 10, and 30 nmol), the OX2r antagonist (TCS OX2 29; 1, 3, 10, and 30 nmol), or a vehicle (0.5 µl solution containing 12% DMSO) through an implanted cannula. Following a 5-min interval, the animals were subjected to a restraint stress (RS) lasting for 3 h. The tail-flick test was conducted after the stress exposure, and the TFLs were assessed at 60-min intervals. The findings of this study revealed that RS elicits antinociceptive responses in the tail-flick test. Microinjection of OX1r and OX2r antagonists into the CA1 attenuated RS-induced analgesia during the tail-flick test. Furthermore, the results underscored the preeminent role of OX2 receptors in modulating SIA. In conclusion, the orexin system localized within the hippocampal CA1 region may, in part, contribute to the manifestation of SIA in the context of acute pain.

Asunto(s)

Benzoxazoles , Región CA1 Hipocampal , Naftiridinas , Antagonistas de los Receptores de Orexina , Receptores de Orexina , Restricción Física , Estrés Psicológico , Animales , Receptores de Orexina/metabolismo , Antagonistas de los Receptores de Orexina/farmacología , Antagonistas de los Receptores de Orexina/administración & dosificación , Masculino , Región CA1 Hipocampal/efectos de los fármacos , Región CA1 Hipocampal/metabolismo , Estrés Psicológico/metabolismo , Ratas , Benzoxazoles/farmacología , Benzoxazoles/administración & dosificación , Naftiridinas/farmacología , Urea/análogos & derivados , Urea/farmacología , Urea/administración & dosificación , Isoquinolinas/farmacología , Isoquinolinas/administración & dosificación , Ratas Sprague-Dawley , Analgésicos/farmacología , Analgésicos/administración & dosificación , Piridinas/farmacología , Piridinas/administración & dosificación , Dolor/tratamiento farmacológico , Dolor/metabolismo , Aminopiridinas , Sulfonamidas

RESUMEN

The complicated relevance between stress and pain has been identified. Neurotransmitters and neuropeptides of various brain areas play a role in this communication. Pain inhibitory response is known as stress-induced analgesia (SIA). The studies demonstrated that the nucleus accumbens (NAc) is critical in modulating pain. As a neuropeptide, orexin is crucially involved in initiating behavioral and physiological responses to threatening and unfeeling stimuli. However, the role of the orexin receptors of the NAc area after exposure to restraint stress (RS) as acute physical stress in the modulation of acute pain is unclear. One hundered twenty adult male albino Wistar rats (230-250 g) were used. Animals were unilaterally implanted with cannulae above the NAc. The SB334867 and TCS OX2 29 were used as antagonists for OX1r and OX2r, respectively. Different doses of the antagonists (1, 3, 10, and 30 nmol/0.5 µl DMSO) were microinjected intra-NAc five minutes before exposure to RS (3 hours). Then, the tail-flick test as a model of acute pain was performed, and the nociceptive threshold (Tail-flick latency; TFL) was measured in 60-minute time set intervals. According to this study's findings, the antinociceptive effects of RS in the tail-flick test were blocked during intra-NAc administration of SB334867 or TCS OX2 29. The RS as acute stress increased TFL and deceased pain-like behavior responses. The 50 % effective dose values of the OX1r and OX2r antagonists were 12.82 and 21.64 nmol, respectively. The result demonstrated contribution of the OX1r into the NAc was more remarkable than that of the OX2r on antinociceptive responses induced by the RS. Besides, in the absence of RS, the TFL was attenuated. The current study's data indicated that OX1r and OX2r into the NAc induced pain modulation responses during RS in acute pain. In conclusion, the findings revealed the involvement of intra-NAc orexin receptors in improving SIA.

Asunto(s)

Dolor Agudo , Benzoxazoles , Naftiridinas , Núcleo Accumbens , Antagonistas de los Receptores de Orexina , Receptores de Orexina , Ratas Wistar , Restricción Física , Estrés Psicológico , Urea , Animales , Núcleo Accumbens/efectos de los fármacos , Núcleo Accumbens/metabolismo , Masculino , Receptores de Orexina/metabolismo , Benzoxazoles/farmacología , Antagonistas de los Receptores de Orexina/farmacología , Antagonistas de los Receptores de Orexina/administración & dosificación , Urea/análogos & derivados , Urea/farmacología , Urea/administración & dosificación , Dolor Agudo/fisiopatología , Dolor Agudo/tratamiento farmacológico , Estrés Psicológico/metabolismo , Estrés Psicológico/fisiopatología , Naftiridinas/farmacología , Isoquinolinas/farmacología , Isoquinolinas/administración & dosificación , Ratas , Piridinas/farmacología , Piridinas/administración & dosificación , Orexinas/farmacología , Orexinas/metabolismo , Relación Dosis-Respuesta a Droga , Dimensión del Dolor/efectos de los fármacos , Aminopiridinas , Sulfonamidas

RESUMEN

Molecular imaging using positron emission tomography (PET) can serve as a promising tool for visualizing biological targets in the brain. Insights into the expression pattern and the in vivo imaging of the G protein-coupled orexin receptors OX1R and OX2R will further our understanding of the orexin system and its role in various physiological and pathophysiological processes. Guided by crystal structures of our lead compound JH112 and the approved hypnotic drug suvorexant bound to OX1R and OX2R, respectively, we herein describe the design and synthesis of two novel radioligands, [18F]KD23 and [18F]KD10. Key to the success of our structural modifications was a bioisosteric replacement of the triazole moiety with a fluorophenyl group. The 19F-substituted analog KD23 showed high affinity for the OX1R and selectivity over OX2R, while the high affinity ligand KD10 displayed similar Ki values for both subtypes. Radiolabeling starting from the respective pinacol ester precursors resulted in excellent radiochemical yields of 93% and 88% for [18F]KD23 and [18F]KD10, respectively, within 20 min. The new compounds will be useful in PET studies aimed at subtype-selective imaging of orexin receptors in brain tissue.

Asunto(s)

Receptores de Orexina , Tomografía de Emisión de Positrones , Receptores de Orexina/metabolismo , Ligandos , Humanos , Relación Estructura-Actividad , Estructura Molecular , Radiofármacos/química , Radiofármacos/síntesis química , Descubrimiento de Drogas , Triazoles/química , Triazoles/síntesis química , Triazoles/farmacología , Radioisótopos de Flúor/química , Antagonistas de los Receptores de Orexina/química , Antagonistas de los Receptores de Orexina/síntesis química , Antagonistas de los Receptores de Orexina/farmacología

RESUMEN

Sleep is considered closely related to cognitive function, and cognitive impairment is the main clinical manifestation of Alzheimer's disease (AD). Sleep disturbance in AD patients is more severe than that in healthy elderly individuals. Additionally, sleep deprivation reportedly increases the activity of the hypothalamic orexin system and the risk of AD. To investigate whether intervention with the orexin system can improve sleep disturbance in AD and its impact on AD pathology. In this study, six-month-old amyloid precursor protein/presenilin 1 mice were subjected to six weeks of chronic sleep deprivation and injected intraperitoneally with almorexant, a dual orexin receptor antagonist (DORA), to investigate the effects and mechanisms of sleep deprivation and almorexant intervention on learning and memory in mice with AD. We found that sleep deprivation aggravated learning and memory impairment and increased brain ß-amyloid (Aß) deposition in mice with AD. The application of almorexant can increase the total sleep time of sleep-deprived mice and reduce cognitive impairment and Aß deposition, which is related to the improvement in Aquaporin-4 polarity. Thus, DORA may be an effective strategy for delaying the progression of AD patients by improving the sleep disturbances.

Asunto(s)

Enfermedad de Alzheimer , Modelos Animales de Enfermedad , Trastornos de la Memoria , Ratones Transgénicos , Antagonistas de los Receptores de Orexina , Privación de Sueño , Animales , Privación de Sueño/complicaciones , Privación de Sueño/tratamiento farmacológico , Ratones , Antagonistas de los Receptores de Orexina/farmacología , Antagonistas de los Receptores de Orexina/uso terapéutico , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/complicaciones , Trastornos de la Memoria/tratamiento farmacológico , Trastornos de la Memoria/etiología , Isoquinolinas/farmacología , Isoquinolinas/uso terapéutico , Precursor de Proteína beta-Amiloide/genética , Acetamidas/farmacología , Acetamidas/uso terapéutico , Masculino , Péptidos beta-Amiloides/metabolismo , Aprendizaje/efectos de los fármacos , Disfunción Cognitiva/tratamiento farmacológico , Disfunción Cognitiva/etiología , Receptores de Orexina/metabolismo , Presenilina-1/genética

RESUMEN

The orexin system consists of the peptide transmitters orexin-A and -B and the G protein-coupled orexin receptors OX1 and OX2 Orexin receptors are capable of coupling to all four families of heterotrimeric G proteins, and there are also other complex features of the orexin receptor signaling. The system was discovered 25 years ago and was immediately identified as a central regulator of sleep and wakefulness; this is exemplified by the symptomatology of the disorder narcolepsy with cataplexy, in which orexinergic neurons degenerate. Subsequent translation of these findings into drug discovery and development has resulted to date in three clinically used orexin receptor antagonists to treat insomnia. In addition to sleep and wakefulness, the orexin system appears to be a central player at least in addiction and reward, and has a role in depression, anxiety and pain gating. Additional antagonists and agonists are in development to treat, for instance, insomnia, narcolepsy with or without cataplexy and other disorders with excessive daytime sleepiness, depression with insomnia, anxiety, schizophrenia, as well as eating and substance use disorders. The orexin system has thus proved an important regulator of numerous neural functions and a valuable drug target. Orexin prepro-peptide and orexin receptors are also expressed outside the central nervous system, but their potential physiological roles there remain unknown. SIGNIFICANCE STATEMENT: The orexin system was discovered 25 years ago and immediately emerged as an essential sleep-wakefulness regulator. This discovery has tremendously increased the understanding of these processes and has thus far resulted in the market approval of three orexin receptor antagonists, which promote more physiological aspects of sleep than previous hypnotics. Further, orexin receptor agonists and antagonists with different pharmacodynamic properties are in development since research has revealed additional potential therapeutic indications. Orexin receptor signaling is complex and may represent novel features.

Asunto(s)

Antagonistas de los Receptores de Orexina , Receptores de Orexina , Humanos , Receptores de Orexina/metabolismo , Receptores de Orexina/fisiología , Animales , Antagonistas de los Receptores de Orexina/farmacología , Antagonistas de los Receptores de Orexina/uso terapéutico , Terminología como Asunto

RESUMEN

BACKGROUND: The orexin (OX) system has received increasing interest as a potential target for treating substance use disorder. OX transmission in the posterior paraventricular nucleus of the thalamus (pPVT), an area activated by highly salient stimuli that are both reinforcing and aversive, mediates cue- and stress-induced reinstatement of reward-seeking behavior. Oral administration of suvorexant (SUV), a dual OX receptor (OXR) antagonist (DORA), selectively reduced conditioned reinstatement of oxycodone-seeking behavior and stress-induced reinstatement of alcohol-seeking behavior in dependent rats. AIMS: This study tested whether OXR blockade in the pPVT with SUV reduces oxycodone or sweetened condensed milk (SCM) seeking elicited by conditioned cues or stress. METHODS: Male Wistar rats were trained to self-administer oxycodone (0.15 mg/kg, i.v., 8 h/day) or SCM (0.1 ml, 2:1 dilution [v/v], 30 min/day). After extinction, we tested the ability of intra-pPVT SUV (15 µg/0.5 µl) to prevent reinstatement of oxycodone or SCM seeking elicited by conditioned cues or footshock stress. RESULTS: The rats acquired oxycodone and SCM self-administration, and oxycodone intake correlated with signs of physical opioid withdrawal, confirming dependence. Following extinction, the presentation of conditioned cues or footshock elicited reinstatement of oxycodone- and SCM-seeking behavior. Intra-pPVT SUV blocked stress-induced reinstatement of oxycodone seeking but not conditioned reinstatement of oxycodone or SCM seeking or stress-induced reinstatement of SCM seeking. CONCLUSIONS: The results indicate that OXR signaling in the pPVT is critical for stress-induced reinstatement of oxycodone seeking, further corroborating OXRs as treatment targets for opioid use disorder.

Asunto(s)

Comportamiento de Búsqueda de Drogas , Antagonistas de los Receptores de Orexina , Orexinas , Oxicodona , Ratas Wistar , Autoadministración , Estrés Psicológico , Animales , Oxicodona/farmacología , Oxicodona/administración & dosificación , Masculino , Ratas , Comportamiento de Búsqueda de Drogas/efectos de los fármacos , Estrés Psicológico/metabolismo , Orexinas/metabolismo , Antagonistas de los Receptores de Orexina/farmacología , Antagonistas de los Receptores de Orexina/administración & dosificación , Señales (Psicología) , Transducción de Señal/efectos de los fármacos , Extinción Psicológica/efectos de los fármacos , Receptores de Orexina/metabolismo , Receptores de Orexina/efectos de los fármacos , Recompensa , Trastornos Relacionados con Opioides/metabolismo , Núcleos Talámicos de la Línea Media/efectos de los fármacos , Núcleos Talámicos de la Línea Media/metabolismo

RESUMEN

Evidence indicates that the use of sedative-hypnotics, including benzodiazepines and z-drugs, is linked to an increased risk of falls and fractures. Nonetheless, the potential exacerbation of this risk by orexin receptor antagonists, which are novel therapeutic agents for treating insomnia, remains uncertain despite their escalating prevalence in clinical practice. We systematically searched four electronic databases from inception to April 17, 2024. In addition, we performed a quality assessment; calculated pooled odds ratios (ORs) to assess the relationship between the use of orexin receptor antagonists and the occurrence of falls or fractures; evaluated heterogeneity across the included studies; and conducted sensitivity analyses. The meta-analysis encompassed eight papers, comprising a total of 46,636 subjects. These papers included 5 case-control studies and 3 randomized controlled trials (RCTs), collectively encompassing ten studies. Analysis of the included case-control studies (pooled adjusted OR = 0.75, 95% confidence interval [CI] = 0.00-1.50, I2 = 66.2%, k = 3) and RCTs (OR = 0.68, 95% CI = 0.31-1.50, I2 = 45.9%, k = 5) indicated that the use of orexin receptor antagonists did not elevate the risk of falls. Similarly, analysis of the included case-control studies revealed no significant increase in the risk of fractures associated with the use of orexin receptor antagonists (pooled adjusted OR = 1.01, 95% CI = 0.82-1.20, I2 = 40.1%, k = 2). This meta-analysis suggests that the use of orexin receptor antagonists for treating insomnia does not escalate the risk of falls or fractures, although the data for lemborexant and daridorexant are limited.

Asunto(s)

Accidentes por Caídas , Fracturas Óseas , Antagonistas de los Receptores de Orexina , Humanos , Accidentes por Caídas/estadística & datos numéricos , Fracturas Óseas/inducido químicamente , Fracturas Óseas/epidemiología , Hipnóticos y Sedantes/efectos adversos , Antagonistas de los Receptores de Orexina/efectos adversos , Antagonistas de los Receptores de Orexina/administración & dosificación , Antagonistas de los Receptores de Orexina/farmacología , Trastornos del Inicio y del Mantenimiento del Sueño/tratamiento farmacológico

RESUMEN

We previously showed that orexin neurons are activated by hypoxia and facilitate the peripheral chemoreflex (PCR)-mediated hypoxic ventilatory response (HVR), mostly by promoting the respiratory frequency response. Orexin neurons project to the nucleus of the solitary tract (nTS) and the paraventricular nucleus of the hypothalamus (PVN). The PVN contributes significantly to the PCR and contains nTS-projecting corticotropin-releasing hormone (CRH) neurons. We hypothesized that in male rats, orexin neurons contribute to the PCR by activating nTS-projecting CRH neurons. We used neuronal tract tracing and immunohistochemistry (IHC) to quantify the degree that hypoxia activates PVN-projecting orexin neurons. We coupled this with orexin receptor (OxR) blockade with suvorexant (Suvo, 20 mg/kg, i.p.) to assess the degree that orexin facilitates the hypoxia-induced activation of CRH neurons in the PVN, including those projecting to the nTS. In separate groups of rats, we measured the PCR following systemic orexin 1 receptor (Ox1R) blockade (SB-334867; 1 mg/kg) and specific Ox1R knockdown in PVN. OxR blockade with Suvo reduced the number of nTS and PVN neurons activated by hypoxia, including those CRH neurons projecting to nTS. Hypoxia increased the number of activated PVN-projecting orexin neurons but had no effect on the number of activated nTS-projecting orexin neurons. Global Ox1R blockade and partial Ox1R knockdown in the PVN significantly reduced the PCR. Ox1R knockdown also reduced the number of activated PVN neurons and the number of activated tyrosine hydroxylase neurons in the nTS. Our findings suggest orexin facilitates the PCR via nTS-projecting CRH neurons expressing Ox1R.

Asunto(s)

Hormona Liberadora de Corticotropina , Neuronas , Antagonistas de los Receptores de Orexina , Receptores de Orexina , Orexinas , Ratas Sprague-Dawley , Núcleo Solitario , Animales , Masculino , Hormona Liberadora de Corticotropina/metabolismo , Orexinas/metabolismo , Ratas , Neuronas/metabolismo , Neuronas/fisiología , Neuronas/efectos de los fármacos , Núcleo Solitario/metabolismo , Núcleo Solitario/fisiología , Núcleo Solitario/efectos de los fármacos , Antagonistas de los Receptores de Orexina/farmacología , Receptores de Orexina/metabolismo , Hipoxia/metabolismo , Triazoles/farmacología , Azepinas/farmacología , Núcleo Hipotalámico Paraventricular/metabolismo , Núcleo Hipotalámico Paraventricular/efectos de los fármacos , Núcleo Hipotalámico Paraventricular/fisiología

RESUMEN

Orexin A and B (OXA and OXB) and their receptors are expressed in the majority of retinal neurons in humans, rats, and mice. Orexins modulate signal transmission between the different layers of the retina. The suprachiasmatic nucleus (SCN) and the retina are central and peripheral components of the body's biological clocks; respectively. The SCN receives photic information from the retina through the retinohypothalamic tract (RHT) to synchronize bodily functions with environmental changes. In present study, we aimed to investigate the impact of inhibiting retinal orexin receptors on the expression of retinal Bmal1 and c-fos, as well as hypothalamic c-fos, Bmal1, Vip, and PACAP at four different time-points (Zeitgeber time; ZT 3, 6, 11, and ZT-0). The intravitreal injection (IVI) of OX1R antagonist (SB-334867) and OX2R antagonist (JNJ-10397049) significantly up-regulated c-fos expression in the retina. Additionally, compared to the control group, the combined injection of SB-334867 and JNJ-10397049 showed a greater increase in retinal expression of this gene. Moreover, the expression of hypothalamic Vip and PACAP was significantly up-regulated in both the SB-334867 and JNJ-10397049 groups. In contrast, the expression of Bmal1 was down-regulated. Furthermore, the expression of hypothalamic c-fos was down-regulated in all groups treated with SB-334867 and JNJ-10397049. Additionally, the study demonstrated that blocking these receptors in the retina resulted in alterations in circadian rhythm parameters such as mesor, amplitude, and acrophase. Finally, it affected the phase of gene expression rhythms in both the retina and hypothalamus, as identified through cosinor analysis and the zero-amplitude test. This study represents the initial exploration of how retinal orexin receptors influence expression of rhythmic genes in the retina and hypothalamus. These findings could provide new insights into how the retina regulates the circadian rhythm in both regions and illuminate the role of the orexinergic system expression within the retina.

Asunto(s)

Hipotálamo , Receptores de Orexina , Polipéptido Hipofisario Activador de la Adenilato-Ciclasa , Proteínas Proto-Oncogénicas c-fos , Retina , Péptido Intestinal Vasoactivo , Animales , Masculino , Ratas , Factores de Transcripción ARNTL/genética , Factores de Transcripción ARNTL/metabolismo , Benzoxazoles/farmacología , Ritmo Circadiano/fisiología , Dioxanos , Regulación de la Expresión Génica , Hipotálamo/metabolismo , Isoquinolinas , Naftiridinas , Antagonistas de los Receptores de Orexina/farmacología , Receptores de Orexina/metabolismo , Receptores de Orexina/genética , Compuestos de Fenilurea , Polipéptido Hipofisario Activador de la Adenilato-Ciclasa/metabolismo , Polipéptido Hipofisario Activador de la Adenilato-Ciclasa/genética , Proteínas Proto-Oncogénicas c-fos/metabolismo , Proteínas Proto-Oncogénicas c-fos/genética , Piridinas , Ratas Wistar , Retina/metabolismo , Núcleo Supraquiasmático/metabolismo , Urea/análogos & derivados , Urea/farmacología , Péptido Intestinal Vasoactivo/metabolismo

RESUMEN

BACKGROUND: The orexin system has been implicated as a mechanism underlying insomnia and methamphetamine-induced sleep disruptions, with a potential role for OX2 receptors in the sleep-modulating effects of orexin. The aim of the present study was to investigate the extent to which orexin receptors mediate the effects of acute methamphetamine administration on actigraphy-based sleep in female rhesus monkeys. METHODS: Actigraphy-based sleep measures were obtained in female rhesus monkeys (n=5) under baseline and acute test conditions. First, morning (10h) i.m. injections of methamphetamine (0.03 - 0.56mg/kg) were administered to determine the effects of methamphetamine alone. Then, saline or methamphetamine (0.3mg/kg) were administered at 10h, and evening (17h30) oral treatments with vehicle, the non-selective orexin receptor antagonist suvorexant (1 - 10mg/kg, p.o.), or the OX2-selective orexin receptor antagonist MK-1064 (1 - 10mg/kg, p.o.) were given. The ability of suvorexant and MK-1064 (10mg/kg, p.o.) to improve actigraphy-based sleep was also assessed in a group of female monkeys quantitatively identified with "short-duration sleep" (n=4). RESULTS: Methamphetamine dose-dependently disrupted actigraphy-based sleep parameters. Treatment with either suvorexant or MK-1064 dose-dependently improved actigraphy-based sleep in monkeys treated with methamphetamine. Additionally, both suvorexant and MK-1064 promoted actigraphy-based sleep in a group of monkeys with baseline short actigraphy-based sleep. CONCLUSIONS: These findings suggest that orexin-mediated mechanisms play a role in the effects of methamphetamine on actigraphy-based sleep in female monkeys. Targeting the orexin system, in particular OX2 receptors, could be an effective option for treating sleep disruptions observed in individuals with methamphetamine use disorder.

Asunto(s)

Actigrafía , Macaca mulatta , Metanfetamina , Antagonistas de los Receptores de Orexina , Receptores de Orexina , Sueño , Animales , Femenino , Metanfetamina/farmacología , Receptores de Orexina/metabolismo , Receptores de Orexina/efectos de los fármacos , Sueño/efectos de los fármacos , Sueño/fisiología , Antagonistas de los Receptores de Orexina/farmacología , Triazoles/farmacología , Azepinas/farmacología , Estimulantes del Sistema Nervioso Central/farmacología , Relación Dosis-Respuesta a Droga

RESUMEN

The orexin system is closely related to the pathogenesis of Alzheimer's disease (AD). Orexin-A aggravates cognitive dysfunction and increases amyloid ß (Aß) deposition in AD model mice, but studies of different dual orexin receptor (OXR) antagonists in AD have shown inconsistent results. Our previous study revealed that OX1R blockade aggravates cognitive deficits and pathological progression in 3xTg-AD mice, but the effects of OX2R and its potential mechanism in AD have not been reported. In the present study, OX2R was blocked by oral administration of the selective OX2R antagonist MK-1064, and the effects of OX2R blockade on cognitive dysfunction and neuropsychiatric symptoms in 3xTg-AD mice were evaluated via behavioral tests. Then, immunohistochemistry, western blotting, and ELISA were used to detect Aß deposition, tau phosphorylation, and neuroinflammation, and electrophysiological and wheel-running activity recording were recorded to observe hippocampal synaptic plasticity and circadian rhythm. The results showed that OX2R blockade ameliorated cognitive dysfunction, improved LTP depression, increased the expression of PSD-95, alleviated anxiety- and depression-like behaviors and circadian rhythm disturbances in 3xTg-AD mice, and reduced Aß pathology, tau phosphorylation, and neuroinflammation in the brains of 3xTg-AD mice. These results indicated that chronic OX2R blockade exerts neuroprotective effects in 3xTg-AD mice by reducing AD pathology at least partly through improving circadian rhythm disturbance and the sleep-wake cycle and that OX2R might be a potential target for the prevention and treatment of AD; however, the potential mechanism by which OX2R exerts neuroprotective effects on AD needs to be further investigated.

Asunto(s)

Enfermedad de Alzheimer , Disfunción Cognitiva , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Ratones Transgénicos , Antagonistas de los Receptores de Orexina , Animales , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/patología , Ratones , Antagonistas de los Receptores de Orexina/farmacología , Disfunción Cognitiva/tratamiento farmacológico , Receptores de Orexina/metabolismo , Péptidos beta-Amiloides/metabolismo , Masculino , Hipocampo/efectos de los fármacos , Hipocampo/patología , Hipocampo/metabolismo

RESUMEN

BACKGROUND AND OBJECTIVES: Daridorexant, a dual orexin receptor antagonist was recently approved for the treatment of insomnia at doses up to 50 mg once per night. This study investigated the effect of single-dose and multiple-dose daridorexant 50 mg at steady state on the pharmacokinetics (PK) of the cytochrome P450 (CYP) 3A4-sensitive substrate midazolam, and the effect of single-dose daridorexant 50 mg on the PK and pharmacodynamics (PD) of the CYP2C9-sensitive substrate warfarin. METHODS: In this prospective, single-center, open-label, fixed-sequence, phase I, drug-drug interaction study, 18 healthy male subjects sequentially received Treatment A, B, and C in three periods. Treatment A consisted of a single oral concomitant administration of midazolam 2 mg and warfarin 25 mg on day 1 of the first period. Treatment B consisted of one oral administration of daridorexant 50 mg followed 1 h later by a single oral dose of midazolam 2 mg concomitantly with a single oral dose of warfarin 25 mg on day 1 and a once-daily oral administration of daridorexant 50 mg for 6 days of the second period. Treatment C consisted of a single oral administration of daridorexant 50 mg at steady state followed 1 h later by a single oral administration of midazolam 2 mg on day 1 of the third period. Blood samples were assessed for midazolam and S-warfarin PK, and PD (international normalized ratio and factor VII). Noncompartmental  PK parameters and PD variables were evaluated with geometric mean ratios and 90% confidence intervals of Treatment B/A versus C/A for midazolam, and treatment B/A for warfarin. Safety and tolerability of each treatment were also assessed. RESULTS: Midazolam maximum plasma concentration (Cmax) and area under the plasma concentration-time curve from 0 to 24 h (AUC0-24) were 1.13- and 1.42-fold higher, respectively, after single-dose administration of daridorexant 50 mg compared to administration of midazolam alone, while Cmax and AUC0-24 were 1.12- and 1.35-fold higher, respectively, after administration of daridorexant 50 mg once daily at steady state. Terminal half-life and time to maximum plasma concentration were comparable between treatments. Daridorexant had no influence on the PK and PD of warfarin. All treatments were safe and well tolerated. CONCLUSIONS: Daridorexant at 50 mg is classified as a weak CYP3A4 inhibitor after single- and multiple-dose administration once daily at steady state. Daridorexant 50 mg did not induce CYP3A4 activity or inhibit CYP2C9 activity. CLINICAL TRIAL REGISTRATION: This trial (NCT05480488) was registered on 29 July, 2022.

Asunto(s)

Interacciones Farmacológicas , Imidazoles , Midazolam , Pirrolidinas , Warfarina , Humanos , Masculino , Midazolam/farmacocinética , Midazolam/administración & dosificación , Adulto , Warfarina/farmacocinética , Warfarina/administración & dosificación , Warfarina/farmacología , Adulto Joven , Voluntarios Sanos , Triazoles/farmacocinética , Triazoles/administración & dosificación , Triazoles/farmacología , Estudios Prospectivos , Antagonistas de los Receptores de Orexina/farmacocinética , Antagonistas de los Receptores de Orexina/farmacología , Antagonistas de los Receptores de Orexina/administración & dosificación , Área Bajo la Curva

Asunto(s)

Trastornos del Inicio y del Mantenimiento del Sueño , Humanos , Trastornos del Inicio y del Mantenimiento del Sueño/tratamiento farmacológico , Orexinas/farmacología , Antagonistas de los Receptores de Orexina/uso terapéutico , Antagonistas de los Receptores de Orexina/farmacología , Sueño

RESUMEN

OBJECTIVE: Test the efficacy of the selective orexin 1 receptor (OX1R) antagonist (SO1RA) nivasorexant in an animal model of binge-eating disorder (BED) and study its dose-response relationship considering free brain concentrations and calculated OX1R occupancy. Compare nivasorexant's profile to that of other, structurally diverse SO1RAs. Gain understanding of potential changes in orexin-A (OXA) neuropeptide and deltaFosB (ΔFosB) protein expression possibly underlying the development of the binge-eating phenotype in the rat model used. METHOD: Binge-like eating of highly palatable food (HPF) in rats was induced through priming by intermittent, repeated periods of dieting and access to HPF, followed by an additional challenge with acute stress. Effects of nivasorexant were compared to the SO1RAs ACT-335827 and IDOR-1104-2408. OXA expression in neurons and neuronal fibers as well as ΔFosB and OXA-ΔFosB co-expression was studied in relevant brain regions using immuno- or immunofluorescent histochemistry. RESULTS: All SO1RAs dose-dependently reduced binge-like eating with effect sizes comparable to the positive control topiramate, at unbound drug concentrations selectively blocking brain OX1Rs. Nivasorexant's efficacy was maintained upon chronic dosing and under conditions involving more frequent stress exposure. Priming for binge-like eating or nivasorexant treatment resulted in only minor changes in OXA or ΔFosB expression in few brain areas. DISCUSSION: Selective OX1R blockade reduced binge-like eating in rats. Neither ΔFosB nor OXA expression proved to be a useful classifier for their binge-eating phenotype. The current results formed the basis for a clinical phase II trial in BED, in which nivasorexant was unfortunately not efficacious compared with placebo. PUBLIC SIGNIFICANCE: Nivasorexant is a new investigational drug for the treatment of binge-eating disorder (BED). It underwent clinical testing in a phase II proof of concept trial in humans but was not efficacious compared with placebo. The current manuscript investigated the drug's efficacy in reducing binge-like eating behavior of a highly palatable sweet and fat diet in a rat model of BED, which initially laid the foundation for the clinical trial.

Asunto(s)

Trastorno por Atracón , Modelos Animales de Enfermedad , Antagonistas de los Receptores de Orexina , Receptores de Orexina , Animales , Antagonistas de los Receptores de Orexina/farmacología , Ratas , Masculino , Trastorno por Atracón/tratamiento farmacológico , Receptores de Orexina/metabolismo , Ratas Sprague-Dawley , Orexinas/metabolismo

RESUMEN

The orexin system consists of two neuropeptides (orexins A and B) and two receptors (OX1 and OX2). Selective OX1 receptor antagonists (SO1RA) are gaining interest for their potential use in the treatment of CNS disorders, including substance abuse, eating, obsessive compulsive, or anxiety disorders. While blocking OX2 reduces wakefulness, the expected advantage of selectively antagonizing OX1 is the ability to achieve clinical efficacy without the promotion of sleep. Herein we report our discovery efforts starting from a dual orexin receptor antagonist and describe a serendipitous finding that triggered a medicinal chemistry program that culminated in the identification of the potent SO1RA ACT-539313. Efficacy in a rat model of schedule-induced polydipsia supported the decision to select the compound as a preclinical candidate. Nivasorexant (20) represents the first SO1RA to enter clinical development and completed a first proof of concept phase II clinical trial in binge eating disorder in 2022.

Asunto(s)

Neuropéptidos , Ratas , Animales , Orexinas , Neuropéptidos/farmacología , Receptores de Orexina , Morfolinas , Antagonistas de los Receptores de Orexina/farmacología , Antagonistas de los Receptores de Orexina/uso terapéutico

Asunto(s)

Enfermedad de Parkinson , Trastornos del Inicio y del Mantenimiento del Sueño , Humanos , Antagonistas de los Receptores de Orexina/farmacología , Antagonistas de los Receptores de Orexina/uso terapéutico , Enfermedad de Parkinson/tratamiento farmacológico , Azepinas/farmacología , Azepinas/uso terapéutico , Triazoles/farmacología , Triazoles/uso terapéutico

RESUMEN

Modulators of orexin receptors are being developed for neurological illnesses such as sleep disorders, addictive behaviours and other psychiatric diseases. We herein describe the discovery of CVN766, a potent orexin 1 receptor antagonist that has greater than 1000-fold selectivity for the orexin 1 receptor over the orexin 2 receptor and demonstrates low off target hits in a diversity screen. In agreement with its in vitro ADME data, CVN766 demonstrated moderate in vivo clearance in rodents and displayed good brain permeability and target occupancy. This drug candidate is currently being investigated in clinical trials for schizophrenia and related psychiatric conditions.

Asunto(s)

Revelación , Trastornos Mentales , Humanos , Orexinas , Antagonistas de los Receptores de Orexina/farmacología , Receptores de Orexina

RESUMEN

The abuse potential of novel CNS-active drug candidates with low specificity for known receptors involved in abuse might be complex to test preclinically relative to an appropriate reference drug of abuse. Suvorexant, a Schedule IV dual orexin receptor antagonist was investigated for its potential use as a reference drug in Drug Discrimination Learning (DDL) studies. Firstly, toxicokinetic properties of suvorexant were determined in male and female rats after single oral doses of 160 and 325 mg/kg in MC and PEG400. Thereafter the subjective effects of suvorexant at 325 mg/kg versus vehicle were evaluated in a DDL paradigm and plasma exposures were measured. Mean maximum plasma exposures in male rats after a single dose of 325 mg/kg suvorexant were 2.5- (MC) to 10.5-fold (PEG400) the human exposure at supratherapeutic doses of 40 mg q.d. (Cmax:1.1 µM), and 4.9- (MC) to 20.8-fold (PEG400) the approved maximum human efficacious dose (20 mg q.d.; 0.557 µM). Training male rats at 325 mg/kg in the DDL study however did not result in discriminative stimulus generalisation versus respective vehicles. Suvorexant, a Schedule IV dual orexin receptor antagonist failed to serve as a robust reference drug of abuse in the DDL paradigm in rats despite appropriate exposures.

Asunto(s)

Azepinas , Antagonistas de los Receptores de Orexina , Humanos , Ratas , Masculino , Femenino , Animales , Antagonistas de los Receptores de Orexina/farmacología , Azepinas/toxicidad , Triazoles