DISCOVERY OF SMALL-MOLECULE ORPHANIN FQ RECEPTOR LIGANDS

描述(申请人提供)：拟议研究的目标是开发新的、选择性的和有效的阿片受体类配体。 受体(ORL1)。ORL1具有与阿片剂密切相关的一级结构 受体有Mu、Delta和kappa。尽管它明显存在于阿片受体中 家族，阿片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止痛。 ORL1及其内源性配体的生理功能， 伤害素/孤儿FQ(N/OFQ)，但很明显， 受体激活可以调节疼痛以及其他中枢神经系统介导的反应。 此外，N/OFQ调节多巴胺和吗啡释放的能力 条件性位置偏爱提示新的ORL1配体的作用是 包括止痛药和成瘾药。这个应用程序描述了一种药物 小分子、高分子化合物的化学设计与鉴定 基于一种新的有效先导的亲和力、选择性ORL1激动剂和拮抗剂 在我们的实验室中使用计算机辅助药物设计和 综合。该方法为构效关系的研究提供了基础 旨在开发新配体的(SAR)和计算机辅助建模研究 用于基于新模板的ORL1。拟合成的化合物将含有 足够的结构变异性来采样ORL1受体结合口袋 从而定义ORL1的药效团，并更好地理解 阿片受体和ORL1结合的差异。所有合成的化合物 将测试ORL1和人类阿片受体的结合亲和力 受体在CHO细胞中表达。功能活动将在两个阶段进行测定 体外实验：刺激[35S]GTP-GammaS与CHO细胞膜结合， 并抑制完整细胞内cAMP的积累。高亲和力和 将测试选择性化合物的N/OFQ类或N/OFQ抑制活性 在小鼠和大鼠中的镇痛，阿片耐受性的调节，以及 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药物，如不上瘾、镇痛剂、抗焦虑药或 药物滥用药物。这些研究应该提供一个更好的理解 ORL1-选择性配体的结构要求及其相似性 以及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正电子发射计算机断层扫描研究的先驱。

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.