G protein-biased kratom-alkaloids and synthetic carfentanil-amide opioids as potential treatments for alcohol use disorder.
2区 · 医学
作者: Anna M Gutridge ; Meridith T Robins ; Robert J Cassell ; Rajendra Uprety ; Kendall L Mores ; Mee Jung Ko ; Gavril W Pasternak ; Susruta Majumdar ; Richard M van Rijn
BACKGROUND AND PURPOSE:
Mitragyna speciosa, more commonly known as kratom, is a plant that contains opioidergic alkaloids, but is unregulated in most countries. Kratom is used in the self-medication of chronic pain and to reduce illicit and prescription opioid dependence. Kratom may be less dangerous than typical opioids because of the stronger preference of kratom alkaloids to induce receptor interaction with G proteins over beta-arrestin proteins. We hypothesized that kratom (alkaloids) can also reduce alcohol intake.
We pharmacologically characterized kratom extracts, kratom alkaloids (mitragynine, 7-hydroxymitragynine, paynantheine, and speciogynine), and synthetic carfentanil-amide opioids for their ability to interact with G proteins and beta-arrestin at mu, delta and kappa opioid receptors in vitro. We used C57BL/6 mice to assess to which degree these opioids could reduce alcohol intake and whether they had rewarding properties.
Kratom alkaloids were strongly G protein-biased at all three opioid receptors and reduced alcohol intake, but kratom and 7-hydroxymitragynine were rewarding. Several results indicated a key role for delta opioid receptors, including that the synthetic carfentanil-amide opioid MP102 - a G protein-biased agonist with modest selectivity for delta opioid receptors - reduced alcohol intake, whereas the G protein-biased mu opioid agonist TRV130 did not.
CONCLUSION AND IMPLICATIONS:
Our results suggest that kratom extracts can decrease alcohol intake, but still carry significant risk upon prolonged use. Development of more delta opioid-selective synthetic opioids may provide a safer option than kratom to treat alcohol use disorder with fewer side effects.
2019-10-01·Talanta2区 · 化学
Development of diffusive gradients in thin films technique for platinum, palladium, and rhodium in natural waters
2区 · 化学
作者: Abdulbur-Alfakhoury, Ehab ; Van Zutphen, Steve ; Leermakers, Martine
The Diffusive Gradients in Thin Films (DGT) technique was developed for the first time for the platinum group elements (PGEs) platinum (Pt), palladium (Pd), and rhodium (Rh). Different chelating resins, specific designed for the accumulation of PGEs, namely Purolite S914, S920, S985, Italmatch Chemicals IONQUEST® MPX-317 and MP-102, were compared. The method development involved several different steps: 1) selection of an appropriate diffusive gel, 2) comparison of resins for the PGEs in terms of kinetics of uptake, 3) development of an efficient elution method for the PGEs from the resin gel, 4) Determination of diffusion coefficients for the PGEs in the diffusive gel, 5) Investigation of the influence of pH, ionic strength and dissolved organic matter on the diffusion coefficients and 6) study the selectivity of the tested resins gels in terms of potential interferences on the determination by ICPMS. Pt, Pd and Rh showed a linear accumulation over time for all resins and diffusion coefficients were independent of pH. The diffusion coefficient for Pt increased with increasing ionic strength (>0.5 M NaCl), but not for Pd and Rh. The interference study showed that Sr was the most important interferent for Rh and Pd and must be removed prior to analysis. The resins Purolite S914, Purolite S920, and Italmatch Chemicals IONQUEST® MPX-317 showed the best performance in terms of detection limits and separation of interferences. Using optimized procedures, the concentrations of Pt, Pd and Rh can be quantified at pg L-1 levels in natural waters for a 14 day deployment time.
1983-01-01·Journal of Antibiotics4区 · 医学
Studies on the biosynthesis of bialaphos (SF-1293). 2. Isolation of the first natural products with a C-P-H bond and their involvement in the C-P-C bond formation
When Streptomyceshygroscopicus SF-1293 was cultivated in the absence of Co2+, 2 compounds (designated MP 101 and MP 102) that contained C-P-H bonds were found in culture filtrates. Both compounds were quant. converted to bialaphos (phosphinothricylalanylanine) by a mutant (NTG-213) blocked at an early step of the bialophos biosynthetic pathway, which indicated that the formation of a P-H bond was a prerequisite for the methylation of P. The structures of MP-101 and MP-102 were determined MP101 at 10 μg/mL inhibited the growth of the producing organism.