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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.

Monoglyceride lipase (MGL) inhibition may offer an approach in treating diseases in which higher 2-arachidonoyglycerol activity would be beneficial. We report here the synthesis and pharmacological evaluation of bis(dialkylaminethiocarbonyl)disulfide derivatives as irreversible MGL inhibitors. Inhibition occurs through interactions with MGL C208 and C242 residues, and these derivatives exhibit high inhibition selectivity over fatty acid amide hydrolase, another endocannabinoid-hydrolyzing enzyme.

This paper reports efforts aimed at tuning up the synthesis of a compound library centered on the general template 2-amino-1-phenyl-2-thioxoethanone taking the condensation of ω-haloacetophenone, octasulfur, and morpholine as pilot reaction. Considerations about atomic economy were found extremely precious in selecting the best starting halo-reagent. A one-pot practical method based on use of 2-bromo-1-phenylethanone as substrate and N,N-dimethylformamide as solvent can be easily scaled up to gram amounts (72% yield). Based on this synthetic approach, some more specific examples are reported.

The purpose of the present work was to determine the identity of the enzymes that synthesize N-acetylaspartylglutamate (NAAG), the most abundant dipeptide present in vertebrate central nervous system (CNS), and β-citrylglutamate, a structural analogue of NAAG present in testis and immature brain. Previous evidence suggests that NAAG is not synthesized on ribosomes but presumably is synthesized by a ligase. As attempts to detect this ligase in brain extracts failed, we searched the mammalian genomes for putative enzymes that could catalyze this type of reaction. Mammalian genomes were found to encode two putative ligases homologous to Escherichia coli RIMK, which ligates glutamates to the C terminus of ribosomal protein S6. One of them, named RIMKLA, is almost exclusively expressed in the CNS, whereas RIMKLB, which shares 65% sequence identity with RIMKLA, is expressed in CNS and testis. Both proteins were expressed in bacteria or HEK293T cells and purified. RIMKLA catalyzed the ATP-dependent synthesis of N-acetylaspartylglutamate from N-acetylaspartate and l-glutamate. RIMKLB catalyzed this reaction as well as the synthesis of β-citrylglutamate. The nature of the reaction products was confirmed by mass spectrometry and NMR. RIMKLA was shown to produce stoichiometric amounts of NAAG and ADP, in agreement with its belonging to the ATP-grasp family of ligases. The molecular identification of these two enzymes will facilitate progress in the understanding of the function of NAAG and β-citrylglutamate.

Montmorillonite K-10 was used in the acid catalysis of the Willgerodt-Kindler’s reaction (WK) under microwave heating for synthesis of thiobenzamides. Yields of 67% and 43% for the synthesis of morpholin- 4- yl (phenyl) methanethione (1) and [4 - (dimethylamino) phenyl] (morpholin-4-yl) methanethione (2) respectively, showed that the mixture (aldehyde, sulfur, morpholine and K-10) is quite suitable for this reaction. This enables to deduct that the conditions of acid catalysis with the K-10 are favourable to the WK’s reaction of carbonyl compounds. Furthermore, yields of 81% and 74% respectively for the synthesis of thioamides 1 and 2 in basic catalysis with 4-methylmorpholine allows to confirm that this reaction is more advantageous in basic catalysis. The structures of thioamides synthesized were characterized and confirmed by spectroscopy Infrared (IR), nuclear magnetic resonance ( 1 H and 13 C NMR) and mass spectrometry (MS). Keywords: Montmorillonite K-10, 4-methylmorpholine, morpholin-4-yl(phenyl)methanethione, [4- (dimethylamino)phenyl](morpholin-4-yl)methanethione