A novel adamantane-type PPAP pain relief molecule with significant Cav3.2 T-type calcium channel inhibition

Polycyclic polyprenylated acylphloroglucinol (PPAP) is a class of natural products with heterozygotic pathways, mainly including bridge ring type, adamantane type and further cracking ring due to the above two architecture types, Rearrangement and sidechain looping of its precursors results in a variety of structurally diverse derivative structure types
.
Among them, adamantane PPAP has long attracted extensive attention from organic chemists and pharmacocologists due to its rigid cage-like structure and molecular framework of drugs, but its activity research lacks new highlights
.
The National Key Experiment on the Structure and Function of Natural Products such as Natural P PAP and Diterpene has long been committed to the study of the structure and function of natural P PAP in Kunming, Chinese Academy of Sciences.
In recent years, through cooperation with the membrane protein (ion channel) natural medicine research group, a series of p-PAP molecules with p-ring and heteroterpene types have significant ion channel activity, and a number of high-level articles have been published (J.
Med.
Chem.
2020, 63, 1709; Org.
Lett.
2020, 22, 6339-6343; Tetrahedron Lett.
2019, 60, 151220), indicating the great potential of P PAP molecules in ion channel activity, and prompting the research team to further try and explore
the ion channel activity of adamantane P PAP molecules.
 

In the in-depth study of the ion channel activity of amantadine-type P PAP, the research team found that the two molecules had a significant inhibitory effect on the Ca_v3.
2 T-type calcium channel, an important target for pain and epilepsy drug development, and a toxic target for the heart at high doses hERG has no obvious effect
.
Among them, compound 1 is a novel adamantane-type P PAP with a novel octahydro-2,5-methanoindene parent nucleus, and its cyclic pathway was analyzed by biogenic pathway with that of conventional adamantane PPAP ( C-7 isoprene group is very different from the C-3 cyclization of the resorcinol parent nucleus and should be derived from C-7 of the bridge ring PPAP The C-4 position of the isoprene group and the resorcinol parent nucleus are cyclized; Its planar structure and absolute configuration were determined by combining spectral data with quantum chemistry calculations (NMR, ECD calculation and DP4+ analysis
).
It is worth pointing out that compound 2 has a better inhibitory effect on Ca_v 3.
2 and _Cav3.
1 Cav3.
3.
It has obvious selectivity
.
In addition, in vivo studies have shown that 2 can significantly inhibit the mouse twisting reaction induced by acetic acid and prolong the time of the first twisting reaction in mice, and its effect is comparable to
that of Z 944, a T-type calcium channel inhibitor currently in clinical trials.
In summary, this study not only discovered a novel type of adamant-type P PAP, but also revealed for the first time that adamantane PPAP has a significant inhibitory effect on Ca v 3.
2.
It also provides a new structural template
for the subsequent development of novel painkillers.
 

Figure 1: Structure of compounds 1 and 2 and their inhibitory effect on _Cav3.
2 T-type calcium channels 

The results end with Cagedpolycyclic polyprenylated acylphloroglucinols as CA_v3.
2 low voltage-gated^{Ca 2+}Channel Inhibitors from Hypericum curvisepalum was published in NatureIndex Journal ChemicalCommunications (DOI: 10.
1039/D2CC05396A.
）
。 Ye Yansong, postdoctoral fellow at Kunming Institute of Botany, Chinese Academy of Sciences, master student Liu Rui and PhD Nana Jiang are co-first authors of the paper, and Xu Gang, researcher and associate researcher Nian Yin of Kunming Institute of Botany, Chinese Academy of Sciences, are co-corresponding authors
of the paper.
The research was supported by the NSFC-Yunnan Provincial Joint Fund (U1902213), the Western Light Intersection Team and Young Scholars Program of the Chinese Academy of Sciences, and the Yunnan Postdoctoral Targeted Training Grant.

 

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