SMALL MOLECULE ORPHANIN FQ/NOCICEPTIN RECEPTOR LIGANDS

描述(申请人摘要)： 孤儿素FQ，十七肽，是一种新发现的天然配体 阿片相关受体。使用这种多肽的氚标记形式， 放射受体结合分析已经用大鼠脑匀浆开发出来。 合成组合文库、模拟多肽文库和多肽文库 将会被检查。杂环库的例子包括双环 取代异喹诺酮、吲哚-咪唑、喹唑烷酮、 环状尿素和海因。在这一过程中合成的新图书馆 这项研究也将进行筛选。激动剂的测定和 确定的任何新配体的拮抗剂性质都将被确定。任何 确定的拮抗剂或激动剂将作为潜在的 治疗学。体内研究表明，孤啡肽FQ可以诱导 对疼痛过敏，被描述为具有抗阿片类药物活性 并已被证明是一种利水剂。三种不同的体外检测方法 将采用：cAMP蓄积试验、GTP结合试验和 小鼠输精管收缩抑制试验。将对拮抗剂进行研究 因为它们能抑制孤啡肽FQ的过敏性痛觉反应。 将对已识别的激动剂化合物进行研究，以了解它们是否具有 孤啡肽FQ(或其代谢物)观察到的延迟镇痛作用， 并将被调查是否有能力诱导水利尿。

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.