Antinociceptive Grayanane Diterpenoids from the Leaves of Pieris japonica

Thirteen new grayanane diterpenoids (1–13) and 15 known analogues (14–28) were isolated from a leaf extract of Pieris japonica. Their structures were determined by spectrometric and spectroscopic methods, including HRESIMS, NMR, IR, and UV. The absolute configurations of 1, 3, 7–9, and 16 were defined by single-crystal X-ray diffraction analysis. 17-Hydroxygrayanotoxin XIX (1) represents the first example of a 17-hydroxygrayan-15(16)-ene diterpenoid. Diterpenoids 1–28 were evaluated for their antinociceptive activities, and 4, 9, 13, 21, and 26–28 displayed significant antinociceptive activities at a dose of 5.0 mg/kg (ip) in the HOAc-induced writhing test in mice. 17-Hydroxygrayanotoxin XIX (1) exhibited potent antinociceptive effects with writhe inhibition rates of 56.3% and 64.8% at doses of 0.04 and 0.2 mg/kg, respectively, which were almost equivalent to the positive control, morphine. Rhodomollein X (26) and rhodojaponin VI (27) showed more potent antinociceptive effects than morphine at doses of 0.04 and 0.2 mg/kg. A preliminary structure–activity relationship for the antinociceptive effects of diterpenoids 1–28 is discussed.