Agonist-Directed MOR Desensitization in Opioid Analgesic Tolerance

描述(申请人提供)：我们之前已经描述了一种新的阿片激动剂，名为Herkinorin，它可以激活u阿片受体，而不需要招募？arrestin2。？抑制素参与阿片受体的脱敏和调节，在小鼠体内清除？？抑制素2可增加吗啡的镇痛效力，同时降低吗啡耐受性。缺乏抑制素2的小鼠也表现出显著减少与吗啡相关的副作用，如便秘和呼吸抑制。因此，开发一种可以激活Mu阿片受体，但不能激活阻止蛋白2相互作用的配基，可能在药理学上概括了吗啡在2基因敲除小鼠中的作用。这类化合物理想的止痛效果是耐受性或副作用非常有限。阿片耐受性与Mu阿片受体脱敏有关。有人会预测，在没有逮捕的情况下，卫生部不会变得不敏感。然而，在细胞中长期使用Herkinorin会导致脱敏的MOR。这一建议是为了评估这种脱敏是否是由于蛋白激酶C依赖的调节机制所致，因为这些激酶以前已经被证明调节u阿片受体的反应。此外，我们将直接测试去激动素是否会导致小鼠的止痛耐受。这类研究对于确定开发不招募止痛药的阿片类激动剂的可行性是必要的，以在没有耐受性和副作用的情况下促进止痛。与公共卫生的相关性：我们的研究旨在探索设计新的阿片类止痛药的可行性，我们预测这种止痛药将产生较少的止痛耐受性，并产生有限的副作用，如便秘和呼吸抑制。我们的研究将基于我们最近描述的一种先导化合物；这种化合物具有非常有希望的生化特性，这将使我们预测它将具有这些有利的特性。

DESCRIPTION (provided by applicant): We have previously described a novel opioid agonist, termed herkinorin, that activates mu opioid receptors without recruiting ?arrestin2. ?arrestins are involved in desensitizing and regulating opioid receptors and the removal ?arrestin2 in mice increases morphine's analgesic potency while attenuating morphine tolerance. Mice that lack ?arrestin2 also display significantly reduced morphine-associated side effects, such as constipation and respiratory suppression. Therefore, the development of a ligand that could activate the mu opioid receptor, but not invoke the ?arrestin2 interaction, may pharmacologically recapitulate the effects of morphine in ?arrestin2 knockout mice. Such compounds would ideally produce analgesia with very limited tolerance or side effects. Opioid tolerance has been associated with the desensitization of the mu opioid receptor. One would predict that in the absence of ?arrestins, the MOR would not be desensitized. However, chronic herkinorin treatment in cells leads to a desensitized MOR. This proposal has been developed to assess whether that desensitization is due to protein kinase C-dependent regulatory mechanisms as these kinases have been previously shown to regulate mu opioid receptor responsiveness. Further, we will directly test whether herkinorin will lead to analgesic tolerance in mice. Such studies are necessary to determine the feasibility of developing opioid agonists that do not recruit ?arrestins to promote analgesia in the absence of tolerance and side effects. The Public Health Relevance: Our studies are designed to explore the feasibility of designing new opioid analgesics that we predict will produce less analgesic tolerance and limited side effects such as constipation and respiratory suppression. We will base our studies on a lead compound that we have recently described; this compound has very promising biochemical properties that would lead us to predict it would possess these favorable characteristics.