Synthesis, characterization and crystal structure of new tetrahydro-β-carboline as acetylcholinesterase inhibitor

In this study, a new tetrahydro-β-carboline derivative, 2-benzoyl-6-methoxy-9-methyl-1-phenyl-1,2,3,4-tetrahydro-β-carboline has been synthesized through a three-steps reaction in good yield (76%). The structure of this compound was characterized by different spectroscopic methods including NMR (1D and 2D), UV, IR and MS. Molecular structure of the synthesized compound was also confirmed by single crystal X-ray diffraction technique. Further, evaluation of in vitro acetylcholinesterase (AChE) inhibitory activity showcased the potential of this compound as AChE inhibitor with an IC50 value of 26.52 ± 0.79 μM. In addition, this compound showed minimal toxicological profile at cellular level. Docking simulation illustrated a highly selective binding at peripheral side of AChE via hydrophobic interactions. In silico prediction of blood-brain barrier (BBB) permeation and ADMET properties of the compound was also reported. © 2019 Elsevier B.V

Rate and extent of mitragynine and 7-hydroxymitragynine blood-brain barrier transport and their intra-brain distribution: : the missing link in pharmacodynamic studies

Mitragyna speciosa is reported to be beneficial for the management of chronic pain and opioid withdrawal in the evolving opioid epidemic. Data on the blood-brain barrier (BBB) transport of mitragynine and 7-hydroxymitragynine, the active compounds of the plant, are still lacking and inconclusive. Here, we present for the first time the rate and the extent of mitragynine and 7-hydroxymitragynine transport across the BBB, with an investigation of their post-BBB intra-brain distribution. We utilized an in vitro BBB model to study the rate of BBB permeation of the compounds and their interaction with efflux transporter P-glycoprotein (P-gp). Mitragynine showed higher apical-to-basolateral (A-B, i.e. blood-to-brain side) permeability than 7-hydroxymitragynine. 7-Hydroxymitragynine showed a tendency to efflux, with efflux ratio (B-A/A-B) of 1.39. Both were found to inhibit the P-gp and are also subject to efflux by the P-gp. Assessment of the extent of BBB transport in vivo in rats from unbound brain to plasma concentration ratios (Kp,uu,brain ) revealed extensive efflux of both compounds, with less than 10 percent of unbound mitragynine and 7-hydroxymitragynine in plasma crossing the BBB. By contrast, the extent of intra-brain distribution was significantly different, with mitragynine having 18-fold higher brain tissue uptake in brain slice assay compared with 7-hydroxymitragynine. Mitragynine showed a moderate capacity to accumulate inside brain parenchymal cells, while 7-hydroxymitragynine showed restricted cellular barrier transport. The presented findings from this systematic investigation of brain pharmacokinetics of mitragynine and 7-hydroxymitragynine are essential for design and interpretation of in vivo experiments aiming to establish exposure-response relationship