Incarvillea sinensis is a natural herb attributed with pain relieving effects. Despite many years of use, its mechanism of action remains debated. One of the key biologically active substituents of incarvillea sinensis is (-)-Incarvillateine (INCA), which shares multiple key structural features with another anti-nociceptive compound, SB-FI 26. One major difference is that INCA is a diester of truxillic acid, whereas SB-FI 26 is a monoester. Since esters are readily hydrolyzed in vivo, a metabolite of INCA would chemically resemble SB-FI 26 even more. Due to similar chemical and biological properties, it was hypothesized that INCA and SB-FI 26 yield anti-nociception via the same mechanism. SB-FI 26 was proven to yield anti-nociception through FABP inhibition, which lead to the postulate that INCA has a similar mechanism of action, especially if one of the ester moieties of INCA is hydrolyzed in vivo. However, in vitro experiments demonstrate neither INCA nor its putative metabolite have appreciable affinity for FABPs. INCA still produced robust anti-nociceptive effects in mouse models, although there was a motor suppression associated with INCA administration. This motor suppression was reversed with administration of an adenosine 2A receptor antagonist, suggesting INCA affinity towards adenosine receptors. The INCA monoester did not produce the same anti-nociception as INCA itself. In order to further investigate the mechanism of INCA anti-nociception, machine learning algorithms and docking programs were applied to INCA and INCA monoester. In silico docking results of INCA and INCA mono ester suggest a poor affinity of both compounds towards FABPs, which was indeed observed in vitro. Docking towards classical anti-nociception targets suggest both INCA and INCA mono ester have affinity for PPAR-γ, Adenosine 2A, Serotonin 1B, and TNF-∝ proteins. These results, as well as the behavioral effects of INCA in vivo, suggest INCA binds to multiple proteins related to nociception.

Biological and computational assessment of (-)-Incarvillateine mechanism of action

2019 Fall National Meeting

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