School of Pharmacy, University of Otago, Dunedin, New Zealand.
Department of Pharmacology and Clinical Pharmacology, University of Auckland, Auckland, New Zealand.
Eur J Med Chem. 2018 Feb 10;145:770-789. doi: 10.1016/j.ejmech.2017.11.076. Epub 2017 Nov 28.
Cannabinoid type 2 (CB) receptor continues to emerge as a promising drug target for many diseases and conditions. New tools for studying CB receptor are required to further inform how this receptor functions in healthy and diseased states. The alkyl indole scaffold is a well-recognised ligand for cannabinoid receptors, and in this study the indole C5-7 positions were explored for linker and fluorophore attachment. A new high affinity, CB receptor selective inverse agonist was identified (16b) along with a general trend of C5-substituted indoles acting as agonists versus C7-substituted indoles acting as inverse agonists. The indole C7 position was found to be the most tolerant to linker extension and resulted in a high affinity inverse agonist with a medium length linker (19). Although a high affinity fluorescent ligand for CB receptor was not identified in this study, the indole C7 position shows great promise for fluorophore or probe attachment.
大麻素类型 2（CB）受体继续成为许多疾病和病症的有前途的药物靶点。需要新的工具来研究 CB 受体，以进一步了解该受体在健康和患病状态下的功能。烷基吲哚支架是大麻素受体的一种公认的配体，在本研究中，吲哚的 C5-7 位置被探索用于连接子和荧光团的连接。发现了一种新的高亲和力、CB 受体选择性反向激动剂（16b），以及 C5 取代的吲哚作为激动剂，而 C7 取代的吲哚作为反向激动剂的一般趋势。吲哚的 C7 位置被发现对连接子的扩展最具耐受性，并导致具有中等长度连接子的高亲和力反向激动剂（19）。尽管在这项研究中没有发现高亲和力的荧光 CB 受体配体，但吲哚的 C7 位置显示出对荧光团或探针连接的巨大潜力。
