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: 6522928
• 负责人: Nurulain T Zaveri
• 金额: $ 50.66万
• 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 2005-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6522928
• 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）：拟议研究的目的是 开发新型的、选择性的和有效的阿片受体样配体， 受体（ORL 1）。ORL 1的一级结构与阿片类物质密切相关 受体μ、δ和κ。虽然它明显存在于阿片受体中 阿片配体不与该受体结合，受体也不与该受体结合。 激活以与其他家族成员相同的方式介导镇痛。 ORL 1及其内源性配体的生理功能， 伤害感受素/FQ中的N/OFQ（N/OFQ）还没有很好地理解，但很明显， 受体活化可以调节疼痛以及其它CNS介导的反应。 此外，N/OFQ调节多巴胺释放的能力以及吗啡 条件性位置偏爱表明，新的ORL 1配体作为 止痛药和成瘾药物。本申请描述了一种药物组合物， 设计和鉴定小分子、高分子、 基于新型强效先导物的亲和性、选择性ORL1激动剂和拮抗剂 在我们的实验室使用计算机辅助药物设计设计的化合物， 合成.该方法为构效关系研究提供了基础 (SAR)和计算机辅助建模研究，旨在开发新的配体 基于新模板的ORL 1。待合成的化合物将含有 足够的结构变异性以采样ORL 1受体结合口袋 从而定义ORL 1的药效团，并更好地理解 阿片受体和ORL 1结合之间的差异。合成的所有化合物 将测试对人的ORL 1和阿片受体的结合亲和力。 在CHO细胞中表达的受体。功能活动将在两个 体外试验：刺激[35S] GTP γ S与CHO细胞膜结合， 和抑制完整细胞中cAMP积累。高亲和力和 将测试选择性化合物的N/OFQ样或N/OFQ抑制活性 在小鼠和大鼠的镇痛模型中，调节阿片耐受性， 加强滥用药物的影响，目的是发展这些 将化合物转化为新的治疗剂作为非成瘾剂、镇痛剂、抗焦虑剂或 滥用药物这些研究应能提供更好的理解 ORL 1-选择性配体的结构要求及其相似性 以及ORL 1和阿片受体之间的差异。作为对我们 为了研究ORL功能，我们还将合成一种已知的高亲和力ORL配体 作为与约翰霍普金斯大学合作进行PET研究的先驱。