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# NM-005683）。GPR55(-/-)（敲除）小鼠的特征揭示了GPR55受体在炎症性疼痛、神经性疼痛和骨骼发育中的作用；而其他研究表明GPR55的激活具有致癌作用。GPR55也可能是一种大麻素受体，因为CB1/CB2激动剂和拮抗剂已被报道作用于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，但目前还没有证实这种受体的低纳摩尔效配体，也没有开发出一种放射性配体来表征这种受体的结合。缺乏此类GPR55配体是该领域进展的关键障碍。在我们的个人实验室与分子文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，我们确定了一系列GPR55拮抗剂，它们属于新的，未报道的GPR55拮抗剂化学型，ic50在0.34至2.72¿M范围内。在这个效价范围内的化合物也被筛选为GPR55的激动剂活性以及GPR35、CB1和CB2的激动剂/拮抗剂活性。重要的是，许多GPR55拮抗剂是完全选择性的，在相关GPR55浓度高达20 μ M的试验中没有观察到活性。我们在此建议利用这些有希望的高含量筛选结果，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，为选定的支架开发SAR，从而鉴定出具有高受体选择性的低纳摩尔IC50 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.