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 (K ) 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.
Guanidinium trichloroacetate (GTCA), a novel organic single crystal was grown by a slow evaporation technique. The single crystal X-ray diffraction study revealed that the GTCA crystal belongs to tetragonal crystal system with the space group P41. From the linear optical studies, the lower cut-off wavelength of grown crystal was found at 257[Formula: see text]nm. The luminescent study showed that the GTCA crystal has high degree of luminescence. The single shot laser damage threshold of grown crystal is found to be 2.6[Formula: see text]GW/cm2. The nonlinear refractive index, absorption coefficient and third-order susceptibility were estimated by Z-scan technique. The two independent tensor coefficients [Formula: see text] of the dielectric permittivity were calculated.
Key indicators: single-crystal X-ray study; T = 293 K; mean (C-C) = 0.002 Å; R factor = 0.048; wR factor = 0.159; data-to-parameter ratio = 21.3.The title compound, C 14 H 16 N 2 O 3 , belongs to a group of esters of 2-oxo-and 1,2,3,4-tetrahydropyrimidine-5-carboxylic acids, which exhibit a wide spectrum of biological activities. The dihydropyrimidine ring adopts a screw-boat conformation. The crystal packing is stabilized by strong N-HÁ Á ÁO and weak C-HÁ Á ÁO intermolecular hydrogen bonds. An intramolecular C-HÁ Á ÁO hydrogen bond is also present.
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Data collectionBruker APEXII CCD area-detector diffractometer Absorption correction: none 16135 measured reflections 3710 independent reflections 2972 reflections with I > 2(I) R int = 0.023
A series of six/five member (E/Z)-Goniothalamin analogs were synthesized from commercially available (3,4-dihydro-2H-pyran-2-yl)methanol/5-(hydroxymethyl)dihydrofuran-2(3H)-one in three steps with good to moderate overall yields and their cytotoxicity against lymphoblastic leukemic T cell line (Jurkat E6.1) have been evaluated. Among the synthesized analogs, (Z)-Goniothalamin appeared to be the most active in cytotoxicity (IC50 = 12 μM). Structure-activity relationship study indicates that introducing substituent in phenyl ring or replacing phenyl ring by pyridine/naphthalene, or decreasing the ring size of lactones (from six to five member) do not increase the cytotoxicity.
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