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Screening of an in-house library of compounds identified 12-thiazole abietanes as a new class of reversible inhibitors of the human metabolic serine hydrolase. Further optimization of the first hit compound lead to the 2methylthiazole derivative 18, with an IC 50 value of 3.4 ± 0.2 μM and promising selectivity. ABHD16A has been highlighted as a new target for inflammation-mediated pain, although selective inhibitors of hABHD16A (human ABHD16A) have not yet been reported. Our study presents abietane-type diterpenoids as an attractive starting point for the design of selective ABHD16A inhibitors, which will contribute toward understanding the significance of hABHD16A inhibition in vivo.

TRPA1 is a non-selective cation channel, most famously expressed in non-myelinated nociceptors.In addition to being an important chemical and mechanical pain sensor, TRPA1 has more recently appeared to have a role in inflammation as well. Triterpenoids are natural products with antiinflammatory and anti-cancer effects in experimental models. In this paper, thirteen novel triterpenoids were created by synthetically modifying betulin, an abundant triterpenoid of the genus Betula L. and their TRPA1-modulating features were examined. Fluo 3-AM protocol was used in the initial screening, in which six out of the fourteen tested triterpenoids inhibited TRPA1 in a statistically significant manner. In subsequent whole-cell patch clamp recordings, the two most effective compounds (pyrazine-fused triterpenoids 8 and 9) displayed a reversible and dose and voltage-dependent effect to block the TRPA1 ion channel at submicromolar concentrations. Interestingly, the TRPA1-blocking action was also evident in vivo, as compounds 8 and 9 both alleviated TRPA1-agonist induced acute paw inflammation in mice. The results introduce betulinderived pyrazine-fused triterpenoids as promising novel antagonists of TRPA1 that are potentially useful in treating diseases with a TRPA1-mediated adverse component.

Despite extensive years of research, the direct oxidation of the 7,8-double bond of opioids has so far received little attention and knowledge about the effects of this modification on activity at the different opioid receptors is scarce. We herein report that potassium permanganate supported on iron(II) sulfate heptahydrate can be used as a convenient oxidant in the one-step, heterogeneous conversion of Δ-opioids to the corresponding 7β-hydroxy-8-ketones. Details of the reaction mechanism are given and the effects of the substituent at position 6 of several opioids on the reaction outcome is discussed. The opioid hydroxy ketones prepared are antagonists at the mu- and delta-opioid receptors. Docking simulations and detailed structure-activity analysis revealed that the presence of the 7β-hydroxy-8-ketone functionality in the prepared compounds can be used to gain activity towards the delta opioid receptor. The 7β-hydroxy-8-ketones prepared with this method can also be regarded as versatile intermediates for the synthesis of other opioids of interest.

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