We compared analgesic activities of individual alkaloids extracted from Baikal aconite (Aconitum baikalensis): napelline, hypaconitine, songorine, mesaconitine, 12-epinapelline N-oxide. The detected analgesic activity was comparable to that of sodium metamizole. The mechanisms of analgesia were different in diterpene alkaloids of different structure. The antinociceptive effect of atisine alkaloids (12-epinapelline N-oxide, songorine) was naloxonedependent and realized via opioid receptor modulation.
The number of candidate
molecules for new non-narcotic analgesics
is extremely limited. Here, we report the identification of thiowurtzine,
a new potent analgesic molecule with promising application in chronic
pain treatment. We describe the chemical synthesis of this unique
compound derived from the hexaazaisowurtzitane (CL-20) explosive molecule.
Then, we use animal experiments to assess its analgesic activity
in vivo
upon chemical, thermal, and mechanical exposures,
compared to the effect of several reference drugs. Finally, we investigate
the potential receptors of thiowurtzine in order to better understand
its complex mechanism of action. We use docking, molecular modeling,
and molecular dynamics simulations to identify and characterize the
potential targets of the drug and confirm the results of the animal
experiments. Our findings finally indicate that thiowurtzine may have
a complex mechanism of action by essentially targeting the mu opioid
receptor, the TRPA1 ion channel, and the Ca
v
voltage-gated
calcium channel.
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