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Kappa Receptor Antagonists as Rapid Acting Antidepressants

Kappa 受体拮抗剂作为速效抗抑郁药

基本信息

批准号：
9753367
负责人：
IRWIN LUCKI
金额：
$ 35.96万
依托单位：
HENRY M. JACKSON FDN FOR THE ADV MIL/MED
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-08-05 至 2021-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9753367
关键词：
AMPA Receptors Acute Amygdaloid structure Anhedonia Animal Behavior Animal Model Anti-Anxiety Agents Antidepressive Agents Anxiety Anxiety Disorders Behavior Behavioral Brain Brain region Brain-Derived Neurotrophic Factor C57BL/6 Mouse Chronic Chronic stress Clinical Treatment Dependence Depression screen Development Disease Dose Drug usage Dynorphins Exposure to FRAP1 gene Fluoxetine Foundations Genetic Goals Injections Ketamine Ligands Major Depressive Disorder Medial Mediating Medical Mental Depression Mental disorders Modeling Moods Morbidity - disease rate Motivation Mus Neuronal Plasticity Nucleus Accumbens Opioid Antagonist Patients Pharmaceutical Preparations Pharmacology Predisposition Prefrontal Cortex Process Production Public Health Receptor Signaling Refractory Research Rewards Role Site Stress Sucrose Testing Therapeutic Therapeutic Effect Time Validation Wild Type Mouse anxiety reduction anxiety-like behavior anxiety-related behavior behavior test clinical development clinical predictors comorbid depression depression model depressive symptoms dysphoria economic impact experimental study forced swim test kappa opioid receptors kappa receptors neural circuit neuromechanism novel novel therapeutics pre-clinical predictive test preference prevent programs public health relevance receptor response treatment-resistant depression

项目摘要

DESCRIPTION (provided by applicant): The overall goal of this research program is to determine whether kappa opioid receptor antagonists have the potential to be developed as rapidly acting antidepressants. There is a clear medical need for new drugs that would expand the options for treating comorbid depression and anxiety, especially for the substantial number of patients refractory to current medications. Kappa opioid receptors and their endogenous ligand dynorphin are thought to be involved in the production of dysphoria and depression accompanying exposure to stress. Kappa opioid receptor antagonists can produce antidepressant and anxiolytic effects in animal models, but the pharmacological profile of existing compounds make them unsuitable for clinical development. The proposed studies would evaluate the effects of two novel kappa opioid receptors, LY2456302 and LY2444295, as potential antidepressant and anxiolytic drugs using animal behavior tests. Studies will determine whether the kappa opioid receptor antagonists produce their effects more rapidly than established antidepressants and similar to ketamine on tests such as the forced swim test, novelty-induced hypophagia and on acutely reversing the effects of chronic mild stress on anhedonia and anxiety. The mechanism of action of kappa opioid receptor antagonists will be confirmed using mice with constitutive deletion of kappa opioid receptors. Additional studies will identify the neural circuitry involved in producing these behavioral effects. Taken together, these experiments will strengthen a basic foundation for considering the development of a novel kappa opioid receptor antagonists as rapid acting antidepressants for eventual therapy in treatment-resistant depression.

描述（由申请人提供）：本研究计划的总体目标是确定κ阿片受体拮抗剂是否有潜力开发为快速作用的抗抑郁药。有一个明确的医疗需要的新药物，将扩大治疗抑郁症和焦虑症共病的选择，特别是对目前的药物难治性的大量患者。κ阿片受体和它们的内源性配体强啡肽被认为参与伴随暴露于压力的烦躁和抑郁的产生。κ阿片受体拮抗剂可以在动物模型中产生抗抑郁和抗焦虑作用，但现有化合物的药理学特征使其不适合临床开发。拟议的研究将使用动物行为试验评估两种新型κ阿片受体LY2456302和LY2444295作为潜在抗抑郁和抗焦虑药物的作用。研究将确定κ阿片受体拮抗剂是否比已建立的抗抑郁药更快地产生作用，并且在强迫游泳试验、新奇感诱导的食欲减退和急性逆转慢性轻度应激对快感缺乏和焦虑的影响等试验中与氯胺酮相似。κ阿片受体拮抗剂的作用机制将使用κ阿片受体组成性缺失的小鼠进行确认。进一步的研究将确定参与产生这些行为效应的神经回路。综上所述各项这些实验将为考虑开发新的κ阿片样物质受体拮抗剂作为快速作用的抗抑郁药用于最终治疗难治性抑郁症奠定基础。