SMALL MOLECULE ORPHANIN FQ/NOCICEPTIN RECEPTOR LIGANDS

描述（申请人摘要）： 孤啡肽FQ，十七肽，是一种新鉴定的 阿片相关受体 使用该肽的氚标记形式， 放射性受体结合分析已经使用大鼠脑匀浆开发。 合成组合文库、拟肽文库和肽文库 将被审查。 杂环库的实例包括双环杂环库。 胍，取代的异喹啉酮，吲哚-咪唑，喹唑啉酮， 环脲和乙内酰脲。 新的图书馆综合过程中， 研究亦会经过筛选。 激动剂的测定和 将确定任何新的配体的拮抗剂性质。 任何 将研究鉴定的拮抗剂或激动剂作为潜在的 治疗学 从体内研究，孤啡肽FQ已显示诱导 对疼痛过敏，被描述为具有抗阿片活性 并被证明是一种利尿剂。 三种不同的体外试验 将采用：cAMP积累测定、GTP结合测定和 小鼠进行输精管收缩抑制试验。 对抗者将是研究 因为它们能够抑制孤啡肽FQ的痛觉过敏作用。 将研究鉴定的激动剂化合物的能力， 通过孤啡肽FQ（或其代谢物）观察到诱导延迟镇痛， 并将研究诱导水利尿的能力。

DESCRIPTION (Applicant's Abstract): Orphanin FQ, heptadecapeptide, is the natural ligand for a newly identified opioid related receptor. Using a tritium labeled form of this peptide, a radioreceptor binding assay has been developed using rat brain homogenates. Synthetic combinatiorial libraries, peptidomimietic and peptide libraries will be examined. Examples of the heterocyclic libraries include bicyclic guanidines, substitute isoquinilones, indole-imidazoles, quinazolinones, cyclic ureas and hydantoins. New libraries synthesized during the course of the study will also be screened. A determination of the agonist and antagonist properties of any new ligands identified will be made. Any identified antagonists or agonists will be investigated as potential therapeutics. From in vivo studies, Orphanin FQ has been shown to induce hypersensitivity to pain, has been described as having anti-opiate activity and has been shown to be a water diuretic. Three different in vitro assays will be employed: a cAMP accumulation assay, a GTP binding assay and a mouse was deferens contraction inhibition assay. Antagonist will be studies for their ability inhibit the hyperalgesic effects of Orphanin FQ. Identified agonist compounds will be investigated for their ability to induce delayed analgesia as observed by Orphanin FQ (or its metabolites), and will be investigated for ability to induce water diuresis.