Pamoic acid analogues as potent GPR35 agoinsts inducing antinociception

描述（由申请人提供）：药物成瘾仍然是美国主要的公共卫生问题。成瘾行为是由于暴露于滥用药物后改变的中枢神经系统信号通路的变化。特别是，大麻素和阿片类药物等影响情绪和疼痛感知的化合物通常与成瘾行为有关。许多调节成瘾的受体是已知的，并且在生物化学上很好地表征，但是一些与已知的滥用受体具有同源性的孤儿受体如GPR35仍然几乎完全未表征。能够选择性抑制或激活孤儿的小分子的鉴定将为阐明成瘾行为的新分子途径提供有利的工具。该提案旨在提供用于表征孤儿G蛋白偶联受体GPR35的新化合物。我们已经使用体外测定鉴定了扑酸类似物作为有效的GPR35激动剂，并且已经发现扑酸诱导抗伤害感受。我们提出了一种策略，以确定主要是市售的小分子，以确定一个有用的分子探针GPR35的目标。优化这些新型化合物将允许在体外和疼痛动物模型中表征GPR35生物学。我们的研究结果表明，帕莫酸意想不到的生物功能和潜在的应用，为新药开发。 公共卫生相关性：该提案将提供描述GPR35药理学的工具，可能为疼痛潜在途径的靶向治疗提供化合物，并澄清我们对GPR35体外生物学和疼痛动物模型的理解。

DESCRIPTION (provided by applicant): Drug addiction continues to remain a major public health concern in the United States. Addictive behavior results from changes in central nervous system signaling pathways that are modified after exposure to drugs of abuse. In particular, compounds such as cannabinoids and opiates that influence mood and pain perception are commonly associated with addictive behaviors. Many receptors regulating addiction are pharmacologically and biochemically well characterized, but some orphan receptors like GPR35 with homology to known receptors of abuse remain almost totally uncharacterized. The identification of small molecules capable of selectively inhibiting or activating orphans will provide enabling tools for elucidating novel molecular pathways underlying addictive behaviors. This proposal seeks to provide new compounds for characterizing the orphan G protein-coupled receptor GPR35. We have identified pamoic acid analogs as potent GPR35 agonists using in vitro assays and have found that pamoic acid induces antinociception. We propose a strategy to identify predominantly commercially available small molecules towards the objective of identifying a useful molecular probe for GPR35. Optimizing these novel compounds will allow the characterization of GPR35 biology in vitro and in animal models of pain. Our results suggest unexpected biological functions of pamoic acid and potential application for new drug development. PUBLIC HEALTH RELEVANCE: This proposal will provide tools for delineating the pharmacology of GPR35, potentially provide compounds for targeted therapeutics of pathways underlying pain, and clarify our understanding of GPR35 biology in vitro and in animal models of pain.