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

描述（由申请人提供）：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、劳动生产率和医疗资源利用率产生了巨大的影响。虽然已经引入非阿片类药物来治疗慢性疼痛综合征，但许多类型的慢性/神经性疼痛对这些药物没有反应（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，特别是？(mu)阿片受体（例如，吗啡、二氢吗啡酮）仍然是慢性疼痛治疗的主要药物。然而，这些？阿片受体靶向药物伴随着非常大的副作用负担，包括因呼吸抑制而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？（kappa）]可以缓解疼痛。此外，已经发现阿片受体可以在细胞表面形成多单元复合物，并且一种受体的活化可以促进这种复合物中另一种受体的活化（正变构相互作用）。利用这一新知识，Lohocla研究公司的实验室合成了一种“合理”设计的分子，它可以激活？然后呢？阿片受体而不受影响受体。这种化合物能止痛。该申请的重点是通过分子建模驱动的药物化学进一步改进该初始（母体）分子。四个新的分子，通过设计，应该有更高的亲和力和效力，作为激动剂？然后呢？受体，将被合成。这些化合物将在受体结合试验和全细胞功能试验中进行检测，以生成特异性特征并确定生物学作用和效价。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I期SBIR研究应该为SBIR II期项目的进一步开发和最有前途的止痛药的临床前工作的完成奠定基础。

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.