A Delta/Kappa OR Ligand: Taking Advantage of Heteromers to Control Pain

描述(申请人提供)：慢性疼痛综合征影响全球25%-35%的人口。慢性疼痛的存在对生活质量、劳动力生产率和医疗资源利用率造成了巨大的损失。虽然非阿片类药物已被引入治疗慢性疼痛综合征，但许多类型的慢性/神经性疼痛对这种药物没有反应(例如，癌症相关疼痛、内脏疼痛综合征)。作用于阿片受体的药物，尤其是？(U)阿片受体(如吗啡、地拉乌德)仍然是慢性疼痛治疗的主要药物。然而，这些呢？阿片受体靶向药物带来了非常严重的副作用负担，包括呼吸抑制导致死亡的风险和对这些化合物的终身身体依赖。最近的研究发现，激活其他类型的阿片受体？(Delta)和？(卡帕)]可以缓解疼痛。此外，人们还发现阿片受体可以在细胞表面形成多单元复合体，其中一个受体的激活可以促进这种复合体中另一个受体的激活(正变构相互作用)。利用这一新知识，Lohocla Research Corporation实验室已经合成了一种“合理”设计的分子，它可以激活？然后呢？阿片受体和不影响吗？感受器。这种化合物可以减轻疼痛。这一应用的重点是通过分子建模驱动的药物化学进一步改进这一初始(母体)分子。四个新分子，根据设计，它们应该作为激动剂具有更高的亲和力和效率？然后呢？受体，将被合成。这些化合物将在受体结合分析和全细胞功能分析中进行测试，以产生特异性特征并确定生物学作用和效力。选定的化合物将用于生物利用度研究，以及在炎症性疼痛综合征动物模型中逆转疼痛的初步概念验证研究。这些第一阶段的SBIR研究应该为通过SBIR第二阶段计划的进一步开发和完成最有希望的止痛药的临床前工作奠定基础。

DESCRIPTION (provided by applicant): Chronic pain syndromes affect 25-35% of populations around the world. The presence of chronic pain generates a massive toll on quality of life, workforce productivity and healthcare resource utilization. Although non-opiate medications have been introduced to treat chronic pain syndromes, many types of chronic/neuropathic pain do not respond to such medications (e.g., cancer-related pain, visceral pain syndromes). Drugs acting at opioid receptors and particularly ? (mu) opioid receptors (e.g., morphine, dilaudid) remain the mainstay of chronic pain therapy. However, these ? opioid receptor targeted drugs carry with them a very substantial burden of side effects, including risk of death by respiratory depression and life- long physical dependence on these compounds. More recent research has discovered that activation of other types of opioid receptors ? (delta) and ? (kappa)] can produce relief from pain. Additionally, it has been discovered that opioid receptors can form multiunit complexes at the cell surface, and activation of one receptor can promote activation of another in such complexes (positive allosteric interaction). Taking advantage of this new knowledge, a "rationally" designed molecule has been synthesized in Lohocla Research Corporation laboratories that can activate ? and ? opiod receptors and not affect ? receptors. This compound alleviates pain. This application is focused on further improvement of this initial (parent) molecule through molecular modeling-driven medicinal chemistry. Four new molecules which, by design, should have higher affinity and efficacy as agonists at ? and ? receptors, will be synthesized. These compounds will be tested in receptor binding assays and whole cell functional assays to generate a specificity profile and determine biological action and potency. Selected compounds will be used for bioavailability studies, and initial proof of concept studies for reversing pain in animal models of inflammatory pain syndromes. These Phase I SBIR studies should set the stage for further development through the SBIR Phase II program and completion of pre-clinical work for a most promising pain medication.