Morphine‐6‐Glucuronide Isomers‐Synthesis and Biological Evaluation

Morphine‐6β‐D‐glucuronide (M6βG), an active metabolite of morphine, and its isomer morphine‐6α‐D‐glucuronide (M6αG) were synthesized from 3‐O‐protected morphinethrough glycosylation and alkaline hydrolysis. All structures were determined by spectroscopic analysis, and especially it is the first time to report the single crystal of compound M6αG. In vitro binding assay showed that M6βG bound to mu opioid receptor (MOR), kappa opioid receptor (KOR), and delta opioid receptor (DOR) with nanomolar affinity (Ki = 28.03, 116.88, and 375.13 nM) and M6αG bound to them with similar affinity (Ki = 1070.13, 20 637.93, and 677.36 nM). The selectivity of M6αG toward KOR is much higher. Hot‐plate test showed that the analgesic effect of M6βG is better than that of M6αG, that is maybe because the mechanism of M6αG is different. In the paper, compound M6βG and M6αG were synthesized, characterized and evaluated. The biological activities of competitive binding assays at MOR, KOR,and DOR showed M6βG and M6αG possessed good affinities for the three opioidreceptors. The selectivity of M6αG towards KOR is much higher. Hot‐platetest showed that the analgesic effect of M6βG is better than that of M6αG, that's maybe because the mechanism of M6αG is different.