DISCOVERY OF SMALL-MOLECULE ORPHANIN FQ RECEPTOR LIGANDS

小分子孤啡肽 FQ 受体配体的发现

• 批准号: 6797925
• 负责人: Nurulain T Zaveri
• 金额: $ 50.69万
• 依托单位: SRI INTERNATIONAL
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-09-30 至 2006-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6797925
• 关键词: CHO cells; analgesia; behavior test; behavioral /social science research tag; chemical structure function; chemical synthesis; chronic pain; computer program /software; conditioning; dopamine; drug design /synthesis /production; drug habituation; intermolecular interaction; laboratory mouse; laboratory rat; ligands; neuropharmacology; nociceptin; nonhuman therapy evaluation; opioid receptor; pharmacokinetics; positron emission tomography; psychomotor function; psychopharmacology; quinolizine

DESCRIPTION (provided by applicant): The objective of the proposed research is to develop novel, selective, and potent ligands for the opiatereceptor-like receptor (ORL1). ORL1 has a primary structure closely related to the opiate receptors, mu, delta and kappa. Although it is clearly in the opiate receptor family, opioid ligands do not bind to this receptor, nor does receptor activation mediate analgesia in the same manner as the other family members. The physiological functions of ORL1 and its endogenous ligand, nociceptin/orphanin FQ (N/OFQ), are not well understood, but it is clear that receptor activation can modulate pain as well as other CNS-mediated responses. In addition, N/OFQ's ability to modulate dopamine release as well as morphine conditioned place preference suggests that a role for novel ORL1 ligands as both pain and addiction medications. This application describes a medicinal chemistry approach to the design and identification of small-molecule, high affinity, selective ORL1 agonists and antagonists, based on a novel potent lead compound designed in our laboratories using computer-assisted drug design and synthesis. Our approach provides a basis for structure activity relationship (SAR) and computer-assisted modeling studies designed to develop new ligands for ORL1 based on novel templates. The compounds to be synthesized will contain sufficient structural variability to sample the ORL1 receptor binding pocket and thus define a pharmacophore for ORL1 and to better understand the differences between opioid receptor and ORL1 binding. All compounds synthesized will be tested for binding affinity at ORL1 and opioid receptors on human receptors expressed in CHO cells. Functional activity will be determined in two in vitro assays: stimulation of [35S]GTPgammaS binding to CHO cell membranes, and inhibition of cAMP accumulation in intact cells. High affinity and selective compounds will be tested for N/OFQ-like or N/OFQ inhibitory activity in mice and rats in models of analgesia, modulation of opiate tolerance, and reinforcing effects of drugs of abuse, with the goal of developing these compounds into novel therapeutics as non-addicting, analgesics, anxiolytics, or drug abuse medications. These studies should provide an improved understanding of the structural requirements for ORL1-selective ligands and the similarities and differences between the ORL1 and opioid receptors. As a complement to our study of ORL function, we will also synthesize a known high affinity ORL ligand as a precursor for PET studies in collaboration with John Hopkins University.

描述（由申请人提供）：拟议的研究的目的是为OpiaTereceptor样子开发新颖，选择性和有效的配体 受体（ORL1）。 ORL1具有与阿片类药物密切相关的主要结构 受体，MU，Delta和Kappa。虽然它显然在阿片受体中 家族，阿片类药物配体不与该受体结合，受体也不结合 激活以与其他家庭成员相同的方式介导镇痛。 ORL1及其内源配体的生理功能， NociTptin/Orphanin FQ（N/OFQ）尚不很好，但很明显 受体激活可以调节疼痛以及其他CNS介导的反应。 此外，N/OFQ调节多巴胺释放以及吗啡的能力 条件地点偏好表明，新型ORL1配体的作用为 疼痛和成瘾药物。该应用描述了药物 化学方法的设计和鉴定小分子高 亲和力，选择性ORL1激动剂和拮抗剂，基于新颖的有效铅 使用计算机辅助的药物设计和实验室设计的化合物 合成。我们的方法为结构活动关系提供了基础 （SAR）和计算机辅助建模研究，旨在开发新的配体 对于基于新型模板的ORL1。要合成的化合物将包含 足够的结构变异性来采样ORL1受体结合袋 从而为ORL1定义了药理，并更好地了解 阿片受体和ORL1结合之间的差异。所有化合物合成 将测试人类ORL1和阿片类受体的结合亲和力 在CHO细胞中表达的受体。功能活性将在两个中确定 体外测定：刺激[35s] gtpgammas与CHO细胞膜结合， 并抑制完整细胞中cAMP的积累。高亲和力和 选择性化合物将用于N/OFQ样或N/OFQ抑制活性 在镇痛模型中的小鼠和大鼠中，鸦片耐受性的调节和 加强滥用药物的影响，目的是开发这些 将新颖的治疗剂作为非成瘾性，镇痛药，抗焦虑药或 药物滥用药物。这些研究应提供改进的理解 ORL1选择配体的结构要求和相似之处 ORL1和阿片受体之间的差异。作为对我们的补充 ORL功能的研究，我们还将合成已知的高亲和力ORL配体 作为与约翰·霍普金斯大学合作的宠物研究的先驱。