hypidone hydrochloride (HHT101) / Zhejiang Huahai Pharma - LARVOL DELTA

Sigma non-opioid intracellular receptor 1 activation relieves post-stroke cognitive impairment via suppressing AIM2-driven inflammatory response. (PubMed, Br J Pharmacol) - "This study highlights the extended therapeutic window for sigma non-opioid intracellular receptor 1 agonist administration during the acute phase of ischaemic stroke and further demonstrates that targeted inhibition of AIM2-mediated neuroinflammatory pathways may promote sustained cognitive rehabilitation in post-stroke survivors."

Journal • Alzheimer's Disease • Cardiovascular • Cognitive Disorders • Inflammation • Ischemic stroke • Melanoma • Oncology • Solid Tumor • AIM2

Hypidone Hydrochloride (YL-0919), a Sigma-1 Receptor Agonist, Improves Attention by Increasing BDNF in mPFC. (PubMed, Pharmaceuticals (Basel)) - "Improving the level of BDNF and dendritic complexity in the mPFC may be the important mechanisms of YL-0919 to improve attention. The study also provides a potential novel target for the drug therapy of attention deficit."

Journal • ADHD (Impulsive Aggression) • Attention Deficit Hyperactivity Disorder • CNS Disorders • Depression • Mood Disorders • Psychiatry • BDNF • DLG4 • Napsin A

The astrocytic sigma-1 receptor constitutes in the fast antidepressant action of hypidone hydrochloride (YL-0919) in rodents. (PubMed, Front Pharmacol) - " Taken together, these results reveal increased BDNF in vHIP by affecting glial cells might be one of the significant mechanisms of fast antidepressant effect of YL-0919. The data provide further evidence for a role of astrocyte receptors in the mechanisms of action of antidepressants."

Journal • Preclinical • CNS Disorders • Depression • Mood Disorders • Psychiatry • BDNF

Neuroprotective effects of hypidone hydrochloride (YL-0919) after traumatic brain injury in mice. (PubMed, Chin Med J (Engl)) - "Our findings indicated that YL-0919 can ameliorate neurological dysfunction in mice after TBI through the suppression of inflammation and the stimulation of the BDNF-mTOR signaling pathway. These findings provide an insightful perspective on the potential pharmacological mechanism involved in the neuroprotective effect of YL-0919."

Journal • Preclinical • CNS Disorders • Cognitive Disorders • Oncology • Vascular Neurology • DLG4 • IL1B • IL4 • Napsin A • TNFA

Hypidone hydrochloride (YL-0919) ameliorates functional deficits after traumatic brain injury in mice by activating the sigma-1 receptor for antioxidation. (PubMed, Neural Regen Res) - "These results indicated that YL-0919 relieved impairments in motor and spatial cognition by restraining oxidative stress, a neuroprotective effect that was partially reversed by the sigma-1 receptor antagonist BD-1047. YL-0919 may have potential as a new treatment for traumatic brain injury."

Journal • Preclinical • CNS Disorders • Vascular Neurology

The role of 5-HTergic neuron activation in the rapid antidepressant-like effects of hypidone hydrochloride (YL-0919) in mice. (PubMed, Front Pharmacol) - "These changes were drastically different from those of the selective serotonin reuptake inhibitor (SSRI) fluoxetine, which suggested that the antidepressant-like effects of the two compounds were mechanistically different. Together, these results reveal a novel role of 5-HTergic neurons in the DRN in mediating the fast-acting antidepressant-like effects of YL-0919, revealing that these neurons are potential novel targets for the development of fast-acting antidepressants for the clinical management of MDD."

Journal • Preclinical • CNS Disorders • Depression • Major Depressive Disorder • Mood Disorders • Psychiatry

Astrocyte-specific inhibition of sigma-1 receptor leads to depressive-like behaviors in mice via activation of NF-κB-induced neuroinflammation. (PubMed, Brain Behav Immun) - "Furthermore, the depressive-like behavior induced by astrocyte-specific knockdown of the σ-1 receptor was improved by a selective NF-κB inhibitor, JSH-23, in mice. Our study not only reaffirms the σ-1 receptor as a key target of the faster antidepressant effect of YL-0919, but also contributes to the development of astrocytic σ-1 receptor-based novel drugs."

Journal • Preclinical • CNS Disorders • Cognitive Disorders • Depression • Inflammation • Major Depressive Disorder • Mood Disorders • Psychiatry

Activation of σ-1 receptor mitigates estrogen withdrawal-induced anxiety/depressive-like behavior in mice via restoration of GABA/glutamate signaling and neuroplasticity in the hippocampus. (PubMed, J Pharmacol Sci) - "YL-0919 rescued the decrease in hippocampal dendritic complexity and spine density induced by estrogen withdrawal. The study results suggest that YL-0919 elicits a therapeutic effect on PPD-like mice; therefore, the σ-1 receptor may be a novel promising target for PPD treatment in the future."

Journal • Preclinical • CNS Disorders • Depression • Mental Retardation • Mood Disorders • Postpartum Depression • Psychiatry

Hypidone hydrochloride (YL-0919) protects mice from meningitis via Sigma1R-STAT1-NLRP3-GSDMD pathway. (PubMed, Int Immunopharmacol) - "These results provide new insights into the mechanisms of inflammation regulation mediated by the antidepressant YL-0919. Moreover, targeting the STAT1/NLRP3 pyroptosis pathway is a promising strategy for the treatment of infectious diseases like bacterial meningitis."

Journal • Preclinical • CNS Disorders • Infectious Disease • Inflammation • Pneumococcal Infections • Pneumonia • NLRP3

A critical step in antidepressants onset: Excitation of glutamatergic pyramidal neurons in rodents' medial prefrontal cortex. (PubMed, Prog Neuropsychopharmacol Biol Psychiatry) - "We found that fluoxetine, duloxetine, vilazodone, YL-0919, and ketamine all increase the firing activities of glutamatergic pyramidal neurons while exerting their antidepressant effects. Furthermore, a significant reduction was observed in the firing activity of pyramidal neurons in the mPFC of CRS-exposed mice, which was reversed by antidepressants. Taken together, our findings suggested that five pharmacologically distinct classes of antidepressants share the common ability to increase the firing activity of pyramidal neurons, which contributes to the body of knowledge of the mechanisms underlying antidepressant effects and paves the way for developing rapid-acting antidepressants."

Journal • Preclinical • CNS Disorders • Depression • Psychiatry

Essential role of microglia in the fast antidepressant action of ketamine and hypidone hydrochloride (YL-0919). (PubMed, Front Pharmacol) - "The microglial depletion of PLX3397 blocked the rapid antidepressant-like effect of ketamine in mice. YL-0919 significantly increased the protein expressions of synapsin-1, PSD-95, GluA1 and BDNF in the PFC, all of which could be blocked by PLX5622. These results suggested the microglia underlying the rapid antidepressant-like effect of ketamine and YL-0919, and microglia would likely constitute in the rapid enhancing impact of synaptic plasticity in the prefrontal cortex by YL-0919."

Journal • BDNF • Napsin A

Astrocytes underlie a faster-onset antidepressant effect of hypidone hydrochloride (YL-0919). (PubMed, Front Pharmacol) - " In our study, mice were exposed to chronic restraint stress (CRS) for 14 days or concomitantly administered YL-0919/fluoxetine. Moreover, YL-0919 improved astrocyte energy metabolism and mitochondrial OXPHOS in astrocytes. Our results provide evidence that YL-0919 exerted a faster-onset antidepressant effect on CRS-mice possibly via astrocyte structural remodeling and mitochondria functional restoration."

Journal • CNS Disorders • Depression • Major Depressive Disorder • Psychiatry

Sigma-1 receptor agonist properties that mediate the fast-onset antidepressant effect of hypidone hydrochloride (YL-0919). (PubMed, Eur J Pharmacol) - "Taken together, the findings of the current study suggest that YL-0919 activates the sigma-1 receptor, which mediates, at least to some extent, the rapid onset antidepressant effects of YL-0919. Thus, YL-0919 is a promising candidate as a fast-onset antidepressant that targets the sigma-1 receptor."

Journal • CNS Disorders • Depression • Major Depressive Disorder • Psychiatry

The effects of Vilazodone, YL-0919 and Vortioxetine in hemiparkinsonian rats. (PubMed, Psychopharmacology (Berl)) - "Collectively, this work supports pharmacological targeting of 5-HT/SERT to reduce L-DOPA-induced dyskinesia. Additionally, this further provides evidence for Vilazodone and Vortioxetine, FDA-approved compounds, as potential adjunct therapeutics for L-DOPA-induced dyskinesia management in Parkinson's patients."

Journal • Preclinical • CNS Disorders • Movement Disorders • Parkinson's Disease

The Effects of Vilazodone, YL-0919 and Vortioxetine in L-DOPA treated hemiparkinsonian rats (Neuroscience 2021) - "Overall, these findings support pharmacological targets within the 5-HT system that reduce LID. They also provide evidence for unique features of Vilazodone and Vortioxetine, both FDA-approved compounds, as potential adjunct therapeutics to optimize L-DOPA treatment for PD patients.; Grant Support: SUNY Technology Accelerator Fund"

Preclinical • CNS Disorders • Parkinson's Disease

New monoamine antidepressant, hypidone hydrochloride (YL-0919), enhances the excitability of medial prefrontal cortex in mice via a neural disinhibition mechanism. (PubMed, Acta Pharmacol Sin) - "Finally, chronic administration of YL-0919 significantly increased the phosphorylation levels of mTOR and GSK-3β in the mPFC as compared with vehicle. Taken together, our results demonstrate that YL-0919 enhances the excitability of mPFC via a disinhibition mechanism to fulfill its rapid antidepressant neural mechanism, which was accomplished by 5-HT receptor-mediated inhibition of inhibitory GABAergic interneurons."

Journal • Preclinical

Tolerability and Pharmacokinetics of Hypidone Hydrochloride in Healthy Subjects (clinicaltrials.gov) - P1; N=36; Completed; Sponsor: Zhejiang Huahai Pharmaceutical Co., Ltd.; Active, not recruiting ➔ Completed

Trial completion • CNS Disorders • Depression • Major Depressive Disorder • Mood Disorders • Psychiatry

Anti-PTSD Effects of Hypidone Hydrochloride (YL-0919): A Novel Combined Selective 5-HT Reuptake Inhibitor/5-HT Receptor Partial Agonist/5-HT Receptor Full Agonist. (PubMed, Front Pharmacol) - "Furthermore, we found that repeated treatment with YL-0919 significantly reversed the accompanying decreased expression of the brain-derived neurotrophic factor (BDNF) and the synaptic proteins (synapsin1 and GluA1), and ameliorated the neuroplasticity disruption in the prefrontal cortex (PFC), including the dendritic complexity and spine density of pyramidal neurons. Taken together, the current study indicated that YL-0919 exerts clear anti-PTSD effects, which might be partially mediated by ameliorating the structural neuroplasticity by increasing the expression of BDNF and the formation of synaptic proteins in the PFC."

Journal • CNS Disorders • Cognitive Disorders • Mood Disorders • Post-traumatic Stress Disorder • Psychiatry • BDNF • Napsin A

The Faster-Onset Antidepressant Effects of Hypidone Hydrochloride (YL-0919) in Monkeys Subjected to Chronic Unpredictable Stress. (PubMed, Front Pharmacol) - "The present study attempted to build a simple and feasible monkey model of depression with chronic unpredictable stress (CUS) and evaluate the antidepressant effect and onset time of fluoxetine hydrochloride (FLX) and the new drug hypidone hydrochloride (YL-0919), a potent and selective 5-HT reuptake inhibitor, 5-HT receptor partial agonist and 5-HT receptor full agonist. Moreover, YL-0919 appeared to act faster than FLX. The present study provides a promising prospect for the evaluation of fast-onset antidepressant drugs based on a CUS monkey model."

Clinical • Journal • CNS Disorders • Depression • Psychiatry • CLSPN,

Tolerability and Pharmacokinetics of Hypidone Hydrochloride in Healthy Subjects (clinicaltrials.gov) - P1; N=36; Active, not recruiting; Sponsor: Zhejiang Huahai Pharmaceutical Co., Ltd.; Not yet recruiting ➔ Active, not recruiting

Clinical • Enrollment closed • CNS Disorders • Depression • Mood Disorders • Psychiatry

Tolerability and Pharmacokinetics of Hypidone Hydrochloride in Healthy Subjects (clinicaltrials.gov) - P1; N=36; Not yet recruiting; Sponsor: Shanghai Synergy Pharmaceutical Sciences Co., Ltd.

Clinical • New P1 trial • CNS Disorders • Depression • Mood Disorders • Psychiatry

The faster-onset antidepressant effects of hypidone hydrochloride (YL-0919). (PubMed, Metab Brain Dis) - "In the CUS rats, it was found that fluoxetine (FLX, 10 mg/kg) treatment exerted antidepressant actions on 20-22d, while YL-0919 or vilazodone (VLZ, a dual 5-HT partial agonist and SSRI) administrated once daily exerted faster antidepressant-like behaviors [4 days in the sucrose preference test (SPT) and 6 days in the novelty suppressed feeding test (NSF)]. Meanwhile, the dendritic complexity of pyramidal neurons in prefrontal cortex (PFC) were also increased in the CUS rats. These data suggest that YL-0919 exerts a faster antidepressant-like effect on behaviors and this effect maybe at least partially mediated by the BDNF-mTOR signaling related dendritic complexity increase in the PFC."

Journal

A hypothesis of monoamine (5-HT) - Glutamate/GABA long neural circuit: Aiming for fast-onset antidepressant discovery. (PubMed, Pharmacol Ther) - "In 2019, the launch of fast-acting antidepressants such as S-ketamine(S-Ket) and brexanolone into market by FDA has opened up new prospects for non-monoamine strategy mainly based on the N-methyl-d-aspartate (NMDA) and γ-aminobutyric acid type A (GABA) receptors...Therefore, five potential strategies are proposed for fast-acting antidepressant based on this circuit: 1) Achieve the rapid E/I balance by relieving the inhibition of GABA interneurons on glutamatergic pyramidal neurons or directly activating pyramidal neurons; 2) Simultaneously modulate 5-HT neuronal activity and Glu/GABA balance by 5-HT transporter combining with some receptors such as 5-HT (namely simultaneous enhancement of the 5-HT and Glu/GABA links); 3) Directly activate mammalian rapamycin target protein complex 1 (mTORC1) and rapidly enhance brain-derived neurotrophic factor (BDNF) -mTOR pathway; 4) Stimulate rapid release of BDNF in the brain; 5) Positive allosteric modulator of synaptic and..."

Journal • Review • BDNF

An ultra HPLC-MS/MS method for quantification of hypidone hydrochloride (YL-0919) and application to a pharmacokinetic study. (PubMed, Bioanalysis) - " A sensitive and robust method was developed and validated for quantitative analysis of YL-0919 in human plasma samples for the first time. And this novel method was successfully applied to investigate pharmacokinetic profiles of YL-0919 in Chinese healthy subjects."

Journal • PK/PD data

Study to Explore the Effective Doses and to Assess the Safety and Efficacy of Hypidone Hydrochloride Tablets (clinicaltrials.gov) - P2; N=240; Completed; Sponsor: Shanghai Synergy Pharmaceutical Sciences Co., Ltd.; Not yet recruiting ➔ Completed

Clinical • Trial completion