Discovery of a novel rosin type T-type calcium channel agonist in Salvia in Kangding

It is an important source of innovative drug research and development to explore novel and active compounds from characteristic medicinal plant groups Salvia is one of the most widely used medicinal plant groups in the world Its genus name Salvia originated from Latin salvare, which means cure And it also has many functions, such as promoting blood circulation and removing blood stasis, activating collaterals and dredging Bi, detoxifying and cooling blood, detumescence and pain relief, antibacterial, nerve stability, headache relief, etc Xu Gang research group, an important group of Phytochemistry and function research team of Kunming Institute of Botany, Chinese Academy of Sciences, has long been engaged in the research of diterpenoid chemical components and biological activities in Salvia plants, and has carried out in-depth research on 12 species of Salvia plants, and has made a series of original achievements, successively in org Lett, More than 20 research papers have been published in the journals of chem Commun And org Chem Front., etc., and many patents have been authorized S prattii can be used as a substitute of S miltiorrhiza in Tibetan medicine, but its chemical composition and function are rarely reported In this study, a pair of novel cis trans tautomers, salpratlactones A and B, derived from the rearrangement of conventional rosin diterpenoids B and C, were found in Salvia in Kangding Different from the 6 / 6 / 6 skeleton of typical rosin diterpenoids, the two compounds have a unique 6-membered 5-membered ring and a γ - lactone ring connected by carbon carbon double bond Generally speaking, CIS and trans isomers in nature keep relatively stable configuration, and only under the condition of heating and other conditions can they change each other It is interesting to note that salpratlactone A and B can undergo a cis trans transition in a proton solvent (such as methanol), but remain stable in an inert solvent (such as chloroform) This is likely to be due to the Michael addition of C-8 / 9 / 7 α, β unsaturated ketone structural fragment and proton solvent, followed by the formation of freely rotatable single bond intermediates at C-8 and C-9 sites, resulting in tautomerism It was found that salpratlactones A and B and their mixtures can enhance the peak current of Ca V 3.1 T-type calcium channel (TTCC) to the same extent, and the enhancement of salpratlactones a to Ca V 3.1 TTCC current is dose-dependent in the concentration range of 1-100 μ m, with EC 50 of 12.48 μ M TTCC (CA V 3.1-3.3) belongs to the low voltage gated calcium channel, which is an important target of drug research and development in pain, amnesia, epilepsy and Parkinson's disease Recent studies have shown that TTCC activators (sak03 and ST101) can improve the cognitive function of Alzheimer's disease (AD) model animals Unlike acetylcholinesterase and NMDA receptor inhibitors, they activate presynaptic T-type calcium channels (CAV) in cholinergic neurons 3.1 and 3.3) can promote the release of acetylcholine, activate the postsynaptic calmodulin dependent protein kinase II (CaMKII), further induce the phosphorylation of rpt6, accelerate the degradation of misfolded proteins such as amyloid - β, so as to achieve the effect of treating AD In addition, TTCC activator ST101 has shown better safety and effectiveness in the United States Ⅱ clinical study of the combination of donepezil and TTCC activator in the treatment of AD Therefore, activation of T-type calcium channel has become a new strategy in the treatment of AD It is worth noting that the synthetic activator sak3 (more active than ST101) only increases the peak current of Ca V 3.1 TTCC by about 20% at the saturation concentration, and does not have a dose effect relationship At 10 μ m, the peak current of cav3.1ttcc can be increased by 30%, while at 100 μ m, the current can be doubled, which shows that the mechanism of salpratlactones a activating cav3.1ttcc is unique, and it is worth further study To sum up, salpratlactone A and B are the first CIS trans isomers of rosin type, and also the first reported natural activator of Ca V 3.1 TTCC In addition, compared with the only two synthetic TTCC like activators, salpratlactone A and B not only have different structural types, but also have different mechanisms of action These findings provide a new structure template for TTCC agonists, and open a new direction for the study of active components of Salvia The above research results were published in the Journal of organizational letters (DOI: 10.1021 / ACS Orglett 9b01527) with the title of "salpratatones A and B: a pair of CIS trans tautomeric abietanes as Ca V 3.1 T-type calcium channel agents from Salvia prattii" Dr Xia fan from Kunming Institute of Botany, Chinese Academy of Sciences and master Li Wenyan from Kunming Institute of zoology, Chinese Academy of sciences are the co authors of this paper Xu Gang, researcher of Kunming Institute of Botany, Chinese Academy of Sciences, Nian Yin, associate researcher of Kunming Institute of zoology, Chinese Academy of Sciences and Li Xian, associate professor of Kunming Medical University are co correspondents.