YNT-185 / University of Tsukuba - LARVOL DELTA

Selective orexin receptor cross-over (SORCO) treatment produces resilience (Neuroscience 2025) - "Thus, we hypothesized that a combination of inhibition of Orx1R (SB-674042) together with activation of Orx2R (YNT-185) would produce enhanced reduction of stress-induced affective behaviors...Treatment with SORCO produces phenotypic reversal (Stay to Escape) by increasing Escape behavior during SAM interactions, more preference during Social Interaction/Preference testing, and less freezing during the Conditioned Response (CR) test. These behavioral adaptations coincide with an increase in Hcrtr1, but not Hcrtr2 mRNA in Rspo2-positive cells of pro-stress circuitry in aBLA."

CNS Disorders • Mood Disorders • Psychiatry • RSPO1 • RSPO2 • SPON1 • SPON2

Cortical layer 6 Drd1a-Cre+ neurons serve as a neuromodulatory hub of cortical arousal by balancing dopaminergic, serotonergic, and orexinergic activation of the murine medial prefrontal cortex (Neuroscience 2025) - "Interestingly, simultaneous application of psilocin and OX2R agonist YNT-185 eliminated the mPFC network activation in control slices by each agonist alone. This suggests a balancing mechanism between 5-HT2AR-expressing and OX2R-expressing L6 neurons in regulating mPFC network activity. Our findings provide novel insight into the role of mPFC L6-Drd1a neurons as a neuromodulatory hub of cortical arousal, with therapeutic implications for anxiety and stress-related disorders."

Preclinical • CNS Disorders • Mood Disorders • Psychiatry • Schizophrenia

Role of orexin receptors in histamine- and chloroquine-induced pruriceptive processing. (PubMed, Neurosci Res) - "It is known that orexin peptides are involved in nociceptive processing, while little is known about the roles of these peptides in itch processing. Scratching events and c-Fos expression induced by histamine, but not CQ, were attenuated by the pretreatment with YNT185. These results indicate that OX-A elicits the attenuating effects in pruriceptive processing and that itch signals induced by histamine and CQ appear to be differentially regulated by the OX2 receptors and OX1 receptors."

Journal • FOS

Attenuated orexinergic signaling underlies sleep-wake problems in a Mecp2-null mouse model of Rett syndrome. (PubMed, Neurobiol Dis) - "Specifically, the expression of hypocretin/orexin receptor (Hcrtr) 1 and 2 genes were significantly lower in several brain regions of Mecp2-null mice, and these mice exhibited attenuated hypocretin/orexin receptor signaling in in vivo microdialysis studies of hypocretin/orexin receptor agonist YNT-185. These results indicate disturbance of the hypocretin/orexin system in Mecp2-null mice, which might cause sleep-wake problems such as increased somnolence in the active phase."

Journal • Preclinical • CNS Disorders • Developmental Disorders • Movement Disorders • Psychiatry • Sleep Disorder

Activation of orexin receptor 2 plays anxiolytic effect in male mice. (PubMed, Brain Res) - "In this study, by using behavioral test, stereotaxic surgery and microinjection, virus-mediated knockdown of OX2R and pharmacological method, we found that: (1) Intraperitoneal injection of OX2R antagonist Seltorexant induced increased baseline anxiety-like behaviors in male mice...(3) Intraperitoneal injection of YNT-185 alleviated morphine withdrawal-induced anxiety-like behaviors in male mice. (4) Microinjection of YNT-185 into the VTA played anxiolytic effect in male mice. (5) Virus-mediated OX2R knockdown in the VTA induced anxiety-like behaviors in male mice."

Journal • Preclinical • CNS Disorders • Mental Retardation • Psychiatry

Involvement of orexin type-2 receptors in genetic absence epilepsy rats. (PubMed, Front Neurol) - "YNT-185 effect on SWDs could be attributed to its regulation of wake/sleep states. The results constitute a step toward understanding the effectiveness of orexin neuropeptides on absence seizures in GAERS and might be targeted by therapeutic intervention for absence epilepsy."

Journal • Preclinical • Absence Seizure Disorder • CNS Disorders • Epilepsy

Face validation and pharmacologic analysis of Sik3 mutant mouse as a possible model of idiopathic hypersomnia. (PubMed, Eur J Pharmacol) - "Moreover, Sleepy mice but not wild-type mice showed a sleep rebound after the orexin-A-induced wakefulness. Intraperitoneal YNT-185 promoted wakefulness for 3 h after injection in Sleepy mice, indicating the potential of using orexin agonists to treat not only orexin deficiency but hypersomnolence of various etiologies."

Journal • Preclinical • CNS Disorders • Sleep Disorder

Dual Cannabinoid and Orexin Regulation of Anhedonic Behaviour Caused by Prolonged Restraint Stress. (PubMed, Brain Sci) - "Restraint mice that received the cannabinoid receptor type 1 (CB1R) antagonist SR141716A, orexin receptor type 2 (OX2R) agonist YNT-185, and the combination of SR141716A and YNT-185, exhibited less anhedonia compared to vehicle/control mice...Although a previous study from our group showed additive cataleptic effects between CP55,940 and the dual orexin receptor antagonist (TCS-1102), the opposite combination of pharmacological agents proved additive for sucrose preference. Taken together, these results reveal more of the complex interactions between the endocannabinoid and orexin systems."

Journal

Contextual generalization of social stress learning is modulated by orexin receptors in basolateral amygdala. (PubMed, Neuropharmacology) - "In Stay mice, freezing in response to social conflict and locomotion during SAM interaction (not home cage locomotion) were generalized to OF, and blocked by intra-BLA OrxR antagonism, but not OrxR antagonism. Moreover, patterns of social avoidance for Escape and Stay mice were recapitulated in OF, with generalization mediated by OrxR and OrxR antagonism, plus OrxR stimulation."

Journal • CNS Disorders • Depression • Mood Disorders • Post-traumatic Stress Disorder • Psychiatry

Design and synthesis of novel orexin 2 receptor agonists based on naphthalene skeleton. (PubMed, Bioorg Med Chem Lett) - "A novel series of naphthalene derivatives were designed and synthesized based on the strategy focusing on the restriction of the flexible bond rotation of OXR selective agonist YNT-185 (1) and their agonist activities against orexin receptors were evaluated...The structure-activity relationship results were well supported by a comparison of the docking simulation results of the most potent derivative 28c with an active state of agonist-bound OXR cryo-EM SPA structure. These results suggested important information for understanding the active conformation and orientation of pharmacophores in the orexin receptor agonists, which is expected as a chemotherapeutic agent for the treatment of narcolepsy."

Journal • Narcolepsy • Sleep Disorder

Discovery of Arylsulfonamides as Dual Orexin Receptor Agonists. (PubMed, J Med Chem) - "We conducted structure-activity relationship studies on the OX2R agonist YNT-185 (2) and discovered dual agonists such as RTOXA-43 (40) with EC's of 24 nM at both OX2R and OX1R...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."

Journal • Cataplexy • Narcolepsy • Sleep Disorder

From orexin receptor agonist YNT-185 to novel antagonists with drug-like properties for the treatment of insomnia. (PubMed, Bioorg Chem) - "Out of them, 15 emerged as the most potent modulator of OXR, which, contrary to YNT-185, displayed inverse mode of action, i.e. antagonist profile. 15 was also submitted to an in vivo experiment revealing its ability to permeate through BBB into the brain with a short half-life."

Journal • CNS Disorders • Insomnia • Narcolepsy • Psychiatry • Sleep Disorder

Exploring the role of orexin B-sirtuin 1-HIF-1α in diabetes-mellitus induced vascular endothelial dysfunction and associated myocardial injury in rats. (PubMed, Life Sci) - "Diabetes-induced significant decline in orexin B levels in the plasma along with a decrease in the expression of sirtuin 1 and HIF-1α in the heart following ischemia-reperfusion injury may possibly contribute in exacerbating the myocardial injury and vascular dysfunction."

Journal • Preclinical • Cardiovascular • Diabetes • Gene Therapies • Ischemic stroke • Metabolic Disorders • Myocardial Infarction • Reperfusion Injury

Activation of orexinergic and histaminergic pathway involved in therapeutic effect of histamine H receptor antagonist against cisplatin-induced anorexia in mice. (PubMed, Naunyn Schmiedebergs Arch Pharmacol) - "Although an OX receptor agonist (YNT-185, 20 mg/kg) or a histamine H receptor inverse agonist (ciproxifan, 1 mg/kg) inhibited the cisplatin-induced anorexia, the inhibitory effect of the OX receptor agonist was antagonized by an H receptor silent antagonist (VUF5681, 5 mg/kg). The combination of JNJ7777120 (10 mg/kg) and ciproxifan (0.5 mg/kg) completely resolved the cisplatin-induced anorexia. These results suggest that activation of the orexinergic and histaminergic pathway is involved in the therapeutic effect of an H receptor antagonist against cisplatin-induced anorexia."

Journal • Preclinical • Anorexia • CNS Disorders • Psychiatry

Effects of an orexin-2 receptor agonist on attention in rats following loss of cortical cholinergic projections (Neuroscience 2019) - "The 100nM dose of YNT-185 improved attentional performance, as compared to the 0nM dose, for rats given the immunotoxin, but worsened performance for rats given saline lesions. YNT-185 may be efficacious in aiding attentional function in animals with vulnerable cholinergic systems but may lead to overexcitation for those with intact cholinergic function."

Preclinical

Increasing the arousal level may inhibit cisplatin-induced anorexia in mice (Neuroscience 2019) - "...Additionally, mice received cisplatin with or without treatment with YNT-185 (an OX2 receptor agonist, 20 mg/kg, s.c.), ciproxifan (an H3 receptor inverse agonist, 1 mg/kg, s.c.), or VUF5681 (an H3 receptor neutral antagonist, 5 mg/kg, s.c.), then their daily food intake was measured...Furthermore, cisplatin decreased the hypothalamic expression of PPO mRNA and the period of expression decreased in parallel with the onset of anorexia. These results suggest that changes in the arousal level may lead to the development of cisplatin-induced anorexia in mice, and the increase of the arousal level via the activation of the orexinergic and histaminergic pathway is involved in the therapeutic effect against cisplatin-induced anorexia."

Preclinical

Nonpeptide Orexin-2 Receptor Agonist Attenuates Morphine-induced Sedative Effects in Rats. (PubMed, Anesthesiology) - "Orexin-A and/or YNT-185 attenuated morphine-induced sedative effects assessed by EEG changes and behavioral measures in rats. The authors' results suggest that orexin-2 receptor activation alleviates morphine-induced sedative effects."

Journal • Preclinical

INVOLVEMENT OF OREXINERGIC AND HISTAMINERGIC SYSTEM IN THERAPEUTIC EFFECT OF HISTAMINE H4 RECEPTOR ANTAGONIST AGAINST CISPLATIN-INDUCED ANOREXIA (MASCC-ISOO 2019) - "Additionally, we examined the effect of YNT-185 (an OX2 receptor agonist), ciproxifan (a histamine H3 receptor inverse agonist), or VUF5681 (an H3 receptor antagonist) on cisplatin-induced anorexia. The activation of the orexinergic and histaminergic pathway is involved in the therapeutic effect of an H4 receptor antagonist against cisplatin-induced anorexia."