Search

Strategies to reduce the misuse of mu opioid agonists are critically needed. Previous work has shown that kappa opioid agonists can diminish the abuse-related effects and augment the antinociceptive effects of mu agonists. However, use of traditional kappa agonists is limited by their dysphoric side effects. The current study examined the effects of nalfurafine, a clinically available atypical kappa agonist, on the reinforcing, thermal antinociceptive, and respiratory-depressant effects of oxycodone in male rats. To determine oxycodone/nalfurafine mixture proportions to be examined intravenously across procedures, a progressive ratio (PR) self-administration procedure compared the reinforcing effects of oxycodone (56 μg/kg/inj) available alone or as a mixture with co-administered nalfurafine (0.32, 1, or 3.2 μg/kg/inj), corresponding to oxycodone/nalfurafine proportions of 175:1, 56:1, and 18:1, respectively. Next, PR and thermal antinociception dose-effect functions were each determined for oxycodone, nalfurafine, and the same oxycodone/nalfurafine mixture proportions. Finally, the respiratory-depressant effects of equi-antinociceptive doses of oxycodone, nalfurafine, and the mixtures were compared. Nalfurafine decreased the reinforcing effects of oxycodone, and the 18:1 mixture did not function as a reinforcer. Oxycodone and nalfurafine each produced dose-dependent antinociception, and the mixtures produced additive antinociception. In addition, antinociceptive doses of the 56:1 and 18:1 mixtures did not produce respiratory depression. These results suggest that nalfurafine may augment the thermal antinociceptive effects while reducing the reinforcing and respiratory-depressant effects of oxycodone.

Thiosemicarbazones have become one of the promising compounds as new clinical candidates due to their wide spectrum of pharmaceutical activities. The wide range of their biological activities depends generally on their related aldehyde or ketone groups. Here, we report the pharmacological activities of some thiosemicarbazones synthesized in this work. Benzophenone and derivatives were used with N(4)-phenyl-3-thiosemicarbazide to synthesize corresponding five thiosemicarbazones (1-5). Their structures were characterized by spectrometrical methods analysis IR, NMR (1)H & (13)C and MS. The compounds were then screened in vitro for their antiparasitic activity and toxicity on Trypanosoma brucei brucei and Artemia salina Leach respectively. The selectivity index of each compound was also determined. Four thiosemicarbazones such as 4, 2, 3 and 1 reveal interesting trypanocidal activities with their half inhibitory concentration (IC50) equal to 2.76, 2.83, 3.86 and 8.48 μM respectively, while compound 5 (IC50 = 12.16 μM) showed a moderate anti-trypanosomal activity on parasite. In toxicity test, except compound 1, which showed a half lethal concentration LC50 >281 μM, the others exerted toxic effect on larvae with LC50 of 5.56, 13.62, 14.55 and 42.50 μM respectively for thiosemicarbazones 4, 5, 3 and 2. In agreement to their selectivity index, which is greater than 1 (SI >1), these compounds clearly displayed significant selective pharmaceutical activities on the parasite tested. The thiosemicarbazones 2-5 that displayed significant anti-trypanosomal and cytoxicity activities are suggested to have anti-neoplastic and anti-cancer activities.

Based on a line of evidence (logP, pKa, 1 H-, and 13 C-NMR, and molecular modeling studies), it appears that cocaine undergoes a hydrophobic collapse which may account for its unprecedented ADME properties, in particular, its exceptional capacity to cross biological membranes. Using molecular simulation techniques, the hypothesis of hydrophobic collapse undergone by the protonated form of cocaine was substantiated using semi-empirical quantum calculations (mainly AM1 and PM3) performed as well as ab initio quantum calculations (6-31 G**). A molecular electrostatic potential map of the internally hydrogen-bonded structure was acquired under AM1 and showed a continuum of high electron density in the central part of the molecule around the methyl ammonium and the two ester moieties. This picture is consistent with the picture of the ammonium being locked between the two C=O and forming a strong canonical primary H bond with the methyl ester and a weaker secondary H bond (non-canonical) with the benzoate ester. Cocaine represents the prototypical example of molecular concision because the pharmacophore and the vector are embedded in the same molecular scaffold. © 2012 Springer Science+Business Media, LLC.

A simpler and efficient “green” method using solid sodium hydroxide in a solvent mixture of acetone/water was found to catalyze N-acylation of 2(3H)-benzoxazolones and 2(3H)-benzothiazolones for facile and rapid synthesis of N-acyl derivatives in excellent yields. This method was applied to the synthesis of a series of 132 compounds employing a variety of acyl chlorides.

Chalcones featuring an analgesic/anti-inflammatory pharmacophore, i.e., the 2(3H)-benzoxazolone heterocycle, on the one hand, and a radical scavenger moiety, i.e., 2,6-di-t-butylphenol, on the other hand were synthesized by condensation of a ketone 2(3H)-benzoxazolone precursor with 3,5-di-t-butyl-4-hydroxybenzaldehyde. Among the various methods explored (acid homogenous or heterogenous catalysis, base catalysis), heterogenous catalysis conditions using KSF Montmorillonite were found to be the most convenient. The E-geometry of the so-obtained chalcones was ascertained both by 1H and 13C-nuclear magnetic resonance (NMR) spectroscopy as well as B3LYP/6-31G** quantum mechanics calculations. Chalcones 1–8 were pharmacologically evaluated in vitro for their ability to prevent human low-density lipoprotein (LDL) copper-induced oxidation using Cu2+ as oxidizing agent. Compound 4 emerged as the most promising agent as it was able to inhibit copper-mediated human LDL oxidation with an activity ten times greater than that of Probucol, a reference antioxidant drug.

Monoglyceride lipase (MGL) is the enzyme responsible for the termination of 2-arachidonoylglycerol (2-AG) signalling, an endogenous ligand for the G-protein coupled cannabinoid receptors CB1 and CB2. Its known abundance and physiological roles emphasize the interest of MGL as an attractive therapeutic target. Search for MGL inhibitors was undertaken by screening an arylthioamide series. The evaluation of arylthioamides derivatives activity as MGL inhibitors measured by the hydrolysis of [H-3]-2-oleoylglycerol by human purified MGL led to the identification of (2-chloro-phenyl)-morpholin-4-yl-methanethione (2) and (3-nitro-phenyl) morpholin-4-yl-methanethione (12), which moreover exhibit good selectivity compared with human fatty acid amide hydrolase inhibition.