Optimization of High Selectivity Antagonist Hits for the GPR55 Receptor

描述（由申请人提供）：GPR55是一种视紫红质样（A类）G蛋白偶联受体（GPCR），在人纹状体中高度表达（Genbank登录号NM-005683）。GPR55（-/-）（敲除）小鼠的表征揭示了GPR55受体在炎性疼痛、神经性疼痛和骨发育中的作用;而其他研究表明GPR55活化是促癌的。GPR55也可能是大麻素受体，因为据报道CB1/CB2激动剂以及拮抗剂作用于GPR55。因此，GPR55也可能在药物滥用中发挥作用。尽管有这些潜在的治疗用途，但尚未证实该受体的低纳摩尔效力配体，也没有开发出放射性配体来表征该受体的结合。缺乏这样的GPR55配体是该领域进展的关键障碍。在我们个人实验室和分子库探针生产中心网络（MLPCN）的Sanford-Burnham筛选中心之间的合作项目中，我们鉴定了一系列GPR55拮抗剂，这些拮抗剂属于新的，未报告的GPR55拮抗剂化学型，IC 50在0.34至2.72 μ M范围内。还筛选了在该效力范围内的化合物的抗GPR 55的激动剂活性以及抗GPR 35、CB 1和CB 2的激动剂/拮抗剂活性沿着。重要的是，许多GPR55拮抗剂是完全选择性的，在浓度高达20 μ M的相关GPCR测定中没有观察到活性。我们在此建议利用这些有希望的高内容筛选结果，使用最先进的基于结构的设计和化学信息学工具结合合成策略来开发所选支架的SAR，从而鉴定出具有高受体选择性的低纳摩尔IC50 GPR55拮抗剂。 公共卫生相关性：叙述摘要GPR55受体是治疗炎性疼痛、神经性疼痛和骨发育障碍的重要新治疗靶点。然而，该受体缺乏低纳摩尔效力配体是该领域进展的关键障碍。这项R21提案的目标是利用我们最近有希望的高通量、高内容的GPR55拮抗剂筛选结果，使用基于结构的设计和化学信息学工具来开发选定支架的SAR，从而鉴定出低纳摩尔IC 50保留高受体选择性的GPR55拮抗剂。

DESCRIPTION (provided by applicant): GPR55 is a rhodopsin-like (Class A) G protein-coupled receptor (GPCR), highly expressed in human striatum (Genbank accession # NM-005683). Characterizations of GPR55(-/-) (knock-out) mice reveal a role for the GPR55 receptor in inflammatory pain, neuropathic pain, and bone development; while other studies indicate that GPR55 activation is pro-carcinogenic. GPR55 may also be a cannabinoid receptor, since CB1/CB2 agonists, as well as antagonists have been reported to act at GPR55. Thus, GPR55 may also have a role to play in drug abuse. Despite these potential therapeutic uses, no low nanomolar potency ligands have been confirmed for this receptor, nor is there a radioligand developed to characterize binding at this receptor. The lack of such GPR55 ligands is a critical barrier to progress in this field. During a collaborative project between our individual laboratoris and the Sanford-Burnham screening center of the Molecular Libraries Probe Production Centers Network (MLPCN), we identified a series of GPR55 antagonists that belong to novel, unreported GPR55 antagonist chemotypes with IC50s in the 0.34 to 2.72 ¿M range. The compounds that were in this potency range were also screened for agonist activity against GPR55 along with agonist/antagonist activity against GPR35, CB1, and CB2. Importantly, many of the GPR55 antagonists were completely selective, with no observed activity in the assays for related GPCRs for concentrations up to 20 ¿M. We propose here to leverage these promising high-content screen results using state-of-the-art structure- based design and cheminformatics tools combined with a synthesis strategy to develop an SAR for selected scaffolds that leads to the identification of low nanomolar IC50 GPR55 antagonists with high receptor selectivity. PUBLIC HEALTH RELEVANCE: NARRATIVE ABSTRACT The GPR55 receptor is an important new therapeutic target for the treatment of inflammatory pain, neuropathic pain, and bone development disorders. However, the lack of low nanomolar potency ligands for this receptor is a critical barrier to progress in this field. The goal of this R21 proposal is to leverge our recent promising high- throughput, high-content screen results for antagonists of GPR55 using structure-based design and cheminformatics tools to develop an SAR for selected scaffolds that leads to the identification of low nanomolar IC50 GPR55 antagonists that retain high receptor selectivity.