Icetexane diterpenoids as Ca v 3.2 T-type calcium channel inhibitors from Salvia prattii and analgesic effect of their Semi-synthesized derivatives

Ten new icetexane diterpenoids, salpratins E–N ( 1 – 10 ) and a known analogue ( 11 ) were characterized from Salvia prattii Hemsl. Structurally, 1 is the first 19(4 → 3)- abeo -icetexane diterpenoid featuring with a 6/7/6 ring system. The structures of isolated compounds were determined by comprehensive analyses of spectroscopic data, ECD calculation, and single-crystal X-ray diffraction. Biological studies initially revealed that 1, 7, 10, and 11 are notable Ca v 3.2 T-type Ca 2+ channel (TTCC) inhibitors with IC 50 values of 2.9, 5.1, 2.3, and 3.2 μM, respectively. Five icetexane related derivatives ( 13 – 17 ) were synthesized from an abietane type precursor, (+)-carnosic acid ( 12 ), for the purpose of overcoming the poor water solubility of aforementioned active compounds and further investigating diverse diterpenes with valuable activity. Among them, 13 and 14 showed potent inhibitions on Ca v 3.2, having IC 50 values of 6.7 and 2.4 μM, respectively. Significantly, they exhibited dose-dependent (1, 3, and 10 mg/kg) and comparable analgesic effects as that of Z944, a TTCCs inhibitor under clinical trial for pain management, in the mouse acetic acid writhing test. These findings further enrich structural diversity and bioactivity of Salvia diterpenoids, as well as provide promising structural templates for the development of Ca v 3.2 analgesics.