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

Delta/Kappa OR 配体：利用异聚物控制疼痛

基本信息

批准号：
8584798
负责人：
Philip Reigan
金额：
$ 15.82万
依托单位：
LOHOCLA RESEARCH CORPORATION
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-07-15 至 2015-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8584798
关键词：
Absence of pain sensation Acute Adenylate Cyclase Adverse effects Affect Affinity Agonist Analgesics Animal Model Binding Biological Biological Assay Biological Availability Blood Blood - brain barrier anatomy Brain Cell membrane Cell surface Cells Cessation of life Characteristics Chemotherapy-Oncologic Procedure Chronic inflammatory pain Clinical Research Complex Data Development Disease Docking Dose Drug Kinetics Drug Targeting Generations Goals Grant Health Care Costs Healthcare High Pressure Liquid Chromatography Hydromorphone In Vitro Inhibitory Concentration 50 Injury Intestines Ion Channel Knowledge Laboratories Life Ligand Binding Ligands Liver Malignant Neoplasms Mass Spectrum Analysis Metabolism Modeling Molecular Molecular Models Molecular Structure Morphine National Institute of Mental Health Opioid Receptor Organ Pain Pain management Parents Permeability Pharmaceutical Chemistry Pharmaceutical Preparations Pharmacologic Substance Phase Physical Dependence Population Preclinical Drug Evaluation Preparation Process Productivity Property Psychotropic Drugs Quality of life Rattus Receptor Activation Research Resources Risk Sampling Services Skeleton Small Business Innovation Research Grant Specificity Staging Structure Study Section Syndrome System Techniques Testing Therapeutic Time TimeLine Toxic effect Ventilatory Depression Visceral pain Work adverse outcome base chronic neuropathic pain chronic pain design in vivo in vivo Model inflammatory pain interest molecular modeling mu opioid receptors novel novel strategies pharmacophore phase 1 study phase 2 study pre-clinical preclinical study programs public health relevance radioligand receptor receptor binding screening uptake

项目摘要

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.

描述（由申请人提供）：慢性疼痛综合症影响着全世界 25-35% 的人口。慢性疼痛的存在会对生活质量、劳动力生产力和医疗资源利用率造成巨大影响。尽管非阿片类药物已被用于治疗慢性疼痛综合征，但许多类型的慢性/神经性疼痛对此类药物没有反应（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、地洛迪）仍然是慢性疼痛治疗的支柱。然而，这些？阿片受体靶向药物会带来非常大的副作用，包括因呼吸抑制而死亡的风险以及对这些化合物的终生身体依赖。最近的研究发现，其他类型的阿片受体的激活？（德尔塔）和？ (kappa)]可以缓解疼痛。此外，还发现阿片受体可以在细胞表面形成多单位复合物，并且一种受体的激活可以促进这种复合物中另一种受体的激活（正变构相互作用）。利用这一新知识，Lohocla 研究公司实验室合成了一种“合理”设计的分子，可以激活？和？阿片受体并没有影响？受体。这种化合物可以减轻疼痛。该应用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。四种新分子，根据设计，作为激动剂应具有更高的亲和力和功效？和？受体，将被合成。这些化合物将在受体结合测定和全细胞功能测定中进行测试，以生成特异性谱并确定生物作用和效力。选定的化合物将用于生物利用度研究，以及逆转炎性疼痛综合征动物模型疼痛的初步概念验证研究。这些 I 期 SBIR 研究应该为通过 SBIR II 期计划进一步开发并完成最有前途的止痛药的临床前工作奠定基础。