Kappa Receptor Antagonists as Rapid Acting Antidepressants

 描述(申请人提供)：这项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作用的抗抑郁药。医学上显然需要新的药物，以扩大治疗并存的抑郁和焦虑的选择，特别是对大量对当前药物无效的患者。Kappa阿片受体及其内源性配体强啡肽被认为参与了伴随压力而产生的烦躁和抑郁的产生。Kappa阿片受体拮抗剂可以在动物模型中产生抗抑郁和缓解焦虑的作用，但现有化合物的药理学特征使其不适合临床开发。拟议的研究将通过动物行为测试来评估两种新型kappa阿片受体LY2456302和LY2444295作为潜在的抗抑郁和抗焦虑药物的效果。研究将确定kappa阿片受体拮抗剂是否在强迫游泳测试、新奇诱导的吞噬减少以及在急性逆转慢性温和应激对快感丧失和焦虑的影响方面比现有的抗抑郁药物和氯胺酮产生更快的效果。Kappa阿片受体拮抗剂的作用机制将在kappa阿片受体结构性缺失的小鼠身上得到证实。更多的研究将确定产生这些行为影响的神经回路。这些加在一起， 实验将为考虑开发一种新型的kappa阿片受体拮抗剂作为最终治疗难治性抑郁症的快速作用抗抑郁剂奠定基础。

 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.