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

• 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
• 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

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）：慢性疼痛综合征影响全球25-35％的人群。慢性疼痛的存在会对生活质量，劳动力生产力和医疗保健资源利用产生巨大损失。尽管已经引入了非伴侣药物来治疗慢性疼痛综合症，但许多类型的慢性/神经性疼痛对这种药物没有反应（例如，与癌症相关的疼痛，内脏疼痛综合症）。作用于阿片类药物受体的药物，特别是？ （MU）阿片受体（例如吗啡，dilaudid）仍然是慢性疼痛疗法的支柱。但是，这些？阿片类药物受体的靶向药物带来了副作用的重大负担，包括呼吸抑郁症死亡的风险以及对这些化合物的寿命长期依赖。最近的研究发现，其他类型的阿片类药物受体的激活？ （三角洲）和？ （kappa）]可以减轻疼痛。此外，已经发现阿片类受体可以在细胞表面形成多卵子复合物，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（阳性变构相互作用）。利用这一新知识，在Lohocla Research Corperation Laboratories中合成了一个“理性”设计的分子，可以激活？和 ？ opiod受体，不影响？受体。这使得减轻了疼痛。该应用集中在通过分子建模驱动的药物化学进一步改善该初始（父）分子。四个新的分子，根据设计，它们应该具有更高的亲和力和功效，因为激动剂在？和 ？受体将合成。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，以产生特异性谱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，以及用于逆转炎症性疼痛综合征疼痛的概念研究证明。这些I期SBIR研究应通过SBIR II期计划和完成前临床工作的完成，为最有前途的止痛药奠定了基础。