Fakhouri Lara, Cook Christopher D, Al-Huniti Mohammed H, Console-Bram Linda M, Hurst Dow P, Spano Michael B S, Nasrallah Daniel J, Caron Marc G, Barak Larry S, Reggio Patricia H, Abood Mary E, Croatt Mitchell P
Department of Chemistry and Biochemistry, Natural Products and Drug Discovery Center, University of North Carolina at Greensboro, Greensboro, NC 27402, United States.
Temple University School of Medicine, Anatomy and Cell Biology, Center for Substance Abuse Research, 3420 North Broad St., Philadelphia, PA 19140, United States.
Bioorg Med Chem. 2017 Aug 15;25(16):4355-4367. doi: 10.1016/j.bmc.2017.06.016. Epub 2017 Jun 13.
GPR55, a G protein-coupled receptor, is an attractive target to alleviate inflammatory and neuropathic pain and treat osteoporosis and cancer. Identifying a potent and selective ligand will aid to further establish the specific physiological roles and pharmacology of the receptor. Towards this goal, a targeted library of 22 compounds was synthesized in a modular fashion to obtain structure-activity relationship information. The general route consisted of coupling a variety of p-aminophenyl sulfonamides to isothiocyanates to form acylthioureas. For the synthesis of a known naphthyl ethyl alcohol motif, route modification led to a shorter and more efficient process. The 22 analogues were analyzed for their ability to serve as agonists at GPR55 and valuable information for both ends of the molecule was ascertained.
GPR55是一种G蛋白偶联受体，是缓解炎症性疼痛和神经性疼痛以及治疗骨质疏松症和癌症的一个有吸引力的靶点。鉴定一种强效且选择性的配体将有助于进一步确定该受体的具体生理作用和药理学特性。为实现这一目标，以模块化方式合成了一个包含22种化合物的靶向文库，以获取构效关系信息。通用路线包括将各种对氨基苯磺酰胺与异硫氰酸酯偶联以形成酰基硫脲。对于已知的萘基乙醇基序的合成，路线改进导致了更短且更有效的过程。分析了这22种类似物作为GPR55激动剂的能力，并确定了该分子两端的有价值信息。
