Target: conolidine

28 May 2011 - Pharma

conolidine_synthesis.svg.png The opioid conolidine can be extracted from the bark of the plant Tabernaemonta divaricata in a meager 0.00014% yield or synthesised in the laboratory as described by Micalizio et al. in a recent Nature Chemistry publication. This plant has a long history of use in traditional medicine in pain relieve and as related compounds such as pericine have already demonstrated efficiency in this area further investigation into conolidine was warranted.

the reported synthesis consisted of 9 steps starting from 1-(pyridin-3-yl)ethanol and 2-lithio-benzenesulfonyl-indole. Pyridine 1 was protected at nitrogen as 2 by p-methoxybenzylchloride enabling its reduction by sodium borohydride to allyl alcohol 3 and addition of tributylstannyl methyl chloride to allyl ether 4. A Wittig rearrangement with BuLi then gave alkene 5 as a cis-trans mix which had to be separated out by collumn chromatography. The Dess-Martin periodinane then reduced the alcohol group to the aldehyde group in 6, nucleophilic addition with organolithium 7 gave alcohol 8, removing the sulfonyl protecting group with sodium amalgam gave 9, oxidation of the alcohol group (manganese dioxide) gave 10 and PMB removal was accomplished using (the very hazardous) chloroethyl chloroformate to free diamine 11. in the final step formaldehyde was added and the resulting imine intermediate 12 formed conolidine 13 (18% overall yield) in a electrophilic aromatic substitution at the indole ring.

The researchers then also synthesised both enantiomers by enzymatic resolution of intermediate 2 and then subjected all three compounds (racemic, natural (+), (-)) to a round of analgesic screening. Unfortunately the only way to do this is by way of animal testing and if you of the animal-loving kind then please step away from your computer monitor now....

And we are back. The animals (mice) must have suffered (especially those in the control group) in making this research possible because yes, the hot plate test and the warm water tail immersion assay (50°C) are exactly what you think they are. More pain was inflicted by injections of acetic acid and formaline. The preliminary results: conolidine is as good as morphine or better and either enantiomer is more effective than the racemate.