Kappa Receptor Antagonists as Rapid Acting Antidepressants

 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。

 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.