Analgesic bisbenzylisoquinoline alkaloids from the rhizoma of Menispermum dauricum DC.

Fifteen new bisbenzylisoquinoline alkaloids (1-15) were isolated from the rhizome of Menispermum dauricum DC. Compounds 1-9 were new N-oxides of dauricine-type alkaloids. Compounds 10-14 were rare tail-to-tail quaternary alkaloids. Their structures were characterized by comprehensive analysis of spectroscopic data, and absolute configurations were established from electronic circular dichroism (ECD) data and ECD calculations. Compounds were assayed on analgesic-related G-protein coupled receptors (GPCRs) including dopamine D1 and D2 receptors, opioid Mu receptor and muscarinic M3 receptor. Compound 1 showed high affinity and selective antagonistic activity on the M3 receptor with an IC value of 2.2 ± 0.5 μM; compound 15 exhibited the highest antagonistic affinity among the evaluated compounds on Mu (IC = 1.1 ± 0.6 μM) and it also acted as a D1 receptor antagonist (IC = 8.8 ± 2.9 μM). These findings expanded the existing library of bisbenzylisoquinoline alkaloids and provided new structures for the related future drug design and synthesis.