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（由适用提供）：该研究计划的总体目标是确定Kappa Ooid受体拮抗剂是否有可能作为快速起作用的抗抑郁药开发。对新药的明显医疗需求将扩大治疗合并抑郁症和焦虑的选择，尤其是对于当前药物难治的大量患者而言。 Kappa Ooid受体及其内源性配体驱虫酚被认为参与了吞咽困难和抑郁症的产生。 Kappa Ooid受体可以在动物模型中产生抗抑郁药和抗焦虑作用，但是现有化合物的药物特征使它们不适合临床发育。拟议的研究将使用动物行为测试评估两种新型的Kappa Ooid受体LY2456302和LY244295的效果为潜在的抗抑郁药和抗焦虑药。研究将确定Kappa Ooid受体拮抗剂是否比已确立的抗抑郁药更快地产生其作用，并且类似于氯胺酮在诸如强制游泳测试，新颖性诱导的下型和急剧逆转慢性轻度应激对抗抗反anthedonia和焦虑的影响的测试中类似。 Kappa Ooid受体拮抗剂的作用机理将使用与构成性缺失Kappa Ooid受体的小鼠确认。其他研究将确定产生这些行为效应的神经回路。总的来说，这些实验将增强考虑新型Kappa阿片受体拮抗剂作为快速起作用抗抑郁药的基本基础，以在治疗抑郁症中最终治疗。