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）：该研究计划的总体目标是确定 kappa 阿片受体拮抗剂是否有潜力被开发为快速起效的抗抑郁药。对于能够扩大治疗共病的选择的新药有明确的医疗需求。抑郁症和焦虑症，尤其是对目前药物治疗无效的大量患者，其内源性配体强啡肽被认为与压力带来的烦躁和抑郁症的产生有关。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。拟议的研究将评估两种新型 kappa 阿片受体 LY2456302 和 LY2444295 作为潜在抗抑郁和抗焦虑药物的作用。通过动物行为测试，研究将确定 kappa 阿片受体拮抗剂是否比现有的抗抑郁药更快地发挥作用，并且与现有的抗抑郁药类似。氯胺酮对强迫游泳试验、新奇事物引起的吞咽不足以及急性逆转慢性轻度应激对快感缺失和焦虑的影响等测试的影响。κ阿片受体拮抗剂的作用机制将通过使用具有κ阿片受体组成性缺失的小鼠来证实。进一步的研究将确定参与产生这些行为效应的神经回路。实验将为考虑开发新型卡帕阿片受体拮抗剂作为速效抗抑郁药以最终治疗难治性抑郁症奠定基础。