Computational study on the conformations of mitragynine and mitragynaline

Abstract

A conformational search on mitragynine and mitragynaline, natural products isolated from the leaves of Mitragyna speciosa, was performed using the MMFF94s force field and the quantum mechanical B3LYP method. The main difference for the mitragynine conformers is caused by the position of the lone pair of the nitrogen shared by rings 3 and 4. Specifically, the lone pair can be syn or anti to the exocylic ethyl group on ring 4. Syn was found to be lower in energy than anti, because of less steric hindrance between the ethyl and the methylene group adjacent to the N in ring 3. The geometrical parameters for the lowest energy conformer of mitragynine are in excellent agreement with the published X-ray crystal structure's geometry. Because it has one more double bond, mitragynaline has less conformational freedom than mitragynine. The main possible conformational choice in mitragynaline is for orientational flexibility of a C-C single bond in ring 3. The finding of two low energy conformers of mitragynaline differing in ring 3 conformation matches reported X-ray crystal structural data.

Kratom: A systematic review of toxicological issues

“…Mitragynine's chemical name is 9‐methoxy‐corynantheidine and its chemical structure is composed of an indole aromatic ring attached to two piperidine rings. Conformational studies suggest that the exocyclic groups have free rotation, while rings A and B are planar (Liu, McCurdy, & Doerksen, 2010). Ring C is a piperidine derivative and the nitrogen is thought to be essential to mitragynine's ability to bind to opioid receptors (Adkins et al, 2011).…”

“…Ring C is a piperidine derivative and the nitrogen is thought to be essential to mitragynine's ability to bind to opioid receptors (Adkins et al, 2011). The methoxy‐moiety at positions C16 and C9 have an open ring with substitution (Liu et al, 2010). Mitragynine has an empirical formula of C 23 H 30 N 2 O 4 (398.5 Da) and the pKa for this weakly basic drug is 8.1 (Ramanathan et al, 2015).…”

Cerebellum and endocannabinoid receptors: a new neurobiological link for mitragynine (Mitragyna speciosa Korth) abuse liability

“…The Methoxy-(MeO) functional group which is present at the ninth carbon of the mitragynine structure is responsible for its anti-nociceptive property [6] . Mitragynine prolonged the latency of nociceptive responses in hot plate, tail pinch test and inhibition of writhing responses [7,11,12] . However, the minor alkaloid, 7-hydroxymitragynine also exhibited anti-nociceptive activities and showed 13 and 46 folds higher activity than morphine and mitragynine respectively [7,13] .…”

In silico investigation of mitragynine and 7-hydroxymitragynine metabolism

“…Conformers of mitragynine derivatives were theoretically studied by Liu et al [13] using MMFF94s force field and B3LYP density functional theory method. Lowest energy structures were confirmed with crystal structures [14–17].…”

“…According to the figure, from left to right, the first and second rings are planar because of their aromaticity but the third and the fourth rings are both in chair conformer. The nitrogen atom between the third and fourth rings is above the plan of the molecule as described by Liu et al [13].…”