Determination of the absolute configuration of 1,3,5-triphenyl-4,5- dihydropyrazole enantiomers by a combination of VCD, ECD measurements, and theoretical calculations

The enantiomers of 1,3,5-triphenyl-4,5-dihydropyrazole (an intense blue fluorescent compound) have been separated for the first time and their absolute configuration was established by a combination of VCD and ECD measurements and theoretical calculations. The enantiomers of 1,3,5-triphenyl-4,5-dihydropyrazole which are highly fluorescent both in solution (CH2Cl2) and in the solid state may find application in the very active field of enantioselective fluorosensors. © 2011 Elsevier Ltd. All rights reserved.Peer Reviewe

1,2,4,5-Tetrazines vs. carboxylic acid dimers: Molecular chemistry vs. supramolecular chemistry

The structures of six new tetrazines have been determined and their molecular packing has been compared to the supermolecular architecture observed in related carboxylic acid dimers. In the tetrazines, covalent N-N bonds are considered to replace the intermolecular O-H⋯O hydrogen bonds of the carboxylic acids. In the systems investigated, it is apparent that, in the majority of cases, the covalent six-membered ring of the tetrazine is an appropriate replacement for the carboxylic acid synthon. This apparent interplay between molecular and supramolecular units may have applications in the crystal engineering of new materials.Peer Reviewe

Therapeutic Exploitation of GPR18: Beyond the Cannabinoids?

GPR18 is a G-protein-coupled receptor that belongs to the orphan class A family. Even though it shares low sequence homology with the cannabinoid receptors CBR and CBR, a growing body of research suggests its relationship with the endocannabinoid system, not only because it is able to recognize cannabinoid ligands but also because of its expression and ability to heteromerize with CBRs. In this review, we aim to analyze the biological relevance, reported modulators, and structural features of GPR18. In order to guide future drug design in this field, highlights from molecular modeling of GPR18 will be provided.P.M., A.L.-F., and N.J. are supported by the Ministry of Science, Innovation, and Universities, Spain (MCIU)/FEDER Grant RTI2018-095544-B-I00, and the Spanish National Research Council (CSIC) Grant PIE-201580E033. M.E.A., P.H.R., and N.J. are supported by National Institutes of Health Grant R01 DA0455698-01. P.M. acknowledges the Comunidad de Madrid (CM) program “Atraccion de Talento” Grant 2018-T2/BMD10819

Palmitoleoylethanolamide is an efficient anti-obesity endogenous compound: Comparison with oleylethanolamide in diet-induced obesity

Obesity is currently a major epidemic in the developed world. However, we lack a wide range of effective pharmacological treatments and therapies against obesity, and those approved are not devoid of adverse effects. Dietary components such as palmitoleic acid have been proposed to improve metabolic disbalance in obesity, although the mechanisms involved are not well understood. Both palmitoleic acid (POA) and oleic acid (OA) can be transformed in N-acylethanolamines (NAEs), mediating the effects of dietary POA and OA. To test this hypothesis, here, we study the effects on food intake and body weight gain of palmitoleylethanolamide (POEA) and the OA-derived NAE analogue, oleoylethanolamide (OEA), in Sprague–Dawley rats with a hypercaloric cafeteria diet (HFD). Plasma biochemical metabolites, inflammatory mediators, and lipogenesis-associated liver protein expression were also measured. The results indicate that POEA is able to improve health status in diet-induced obesity, decreasing weight, liver steatosis, inflammation, and dyslipemia. The action of POEA was found to be almost identical to that of OEA, which is an activator of the nuclear peroxisome proliferator receptor alpha (PPARα), and it is structurally related to POEA. These results suggest that the dietary administration of either POA or POEA might be considered as nutritional intervention as complementary treatment for complicated obesity in humans

Exploring the Orphan GPCR GPR18 through Novel Synthetic Cannabidiol Derivatives

GPR18 is an orphan GPCR highly expressed in lymphoid tissues and the central nervous system that regulates cellular migration, proliferation, nociociception, and immunomodulation. The endocannabinoid derivative N-Arachidonoylglycine (NAGly) has been proposed as the putative ligand. Several other cannabinoids also interact with GPR18, such as Abn-CBD and ¿9-THC. However, very few potent synthetic GPR18 ligands have been described so far. A new family of compounds with a cannabidiol scaffold were designed to target GPR18. Calcium mobilization imaging studies1 and docking studies in a in silico model2 were used to evaluate the activity of compounds and their mechanism of action. Here, two of the best compounds are exemplified: S5, a GPR18 agonist, and S4, a GPR18 antagonist

A critical review of both the synthesis approach and the receptor profile of the 8-chloro-1-(2′,4′-dichlorophenyl)-N-piperidin-1-yl-1,4,5,6-Tetrahydrobenzo[6,7] cyclohepta[1,2-c ]pyrazole-3-carboxamide and analogue derivatives

8-Chloro-1-(2′,4′-dichlorophenyl)-N-piperidin-1-yl-1,4,5,6-Tetrahydrobenzo[6,7]cyclohepta[1,2-c]pyrazole-3-carboxamide 9a was discovered as potent and selective CB1 antagonist by part of our group few years ago. In particular it was reported to have an affinity towards the CB1 cannabinoid receptor (CB1R), expressed as Ki, of 0.00035 nM. Nevertheless significantly divergent data were reported for the same compound from other laboratories. To unequivocally define the receptor profile of 9a, we have critically reviewed both its synthesis approach and binding data. Here we report that, in contrast to our previously reported data, 9a showed a Ki value for CB1R in the order of nanomolar rather than of fentomolar range. The new determined receptor profile of 9a was also ascertained for analogue derivatives 9b-i, as well as for 12. Moreover, the structural features of the synthesized compounds necessary for CB1R were investigated. Amongst the novel series, effects on CB1R intrinsic activity was highlighted due to the substituents at the position 3 of the pyrazole ring of the 1,4,5,6-Tetrahydrobenzo[6,7]cyclohepta[1,2-c]pyrazole scaffold.Although the cannabinoid receptor profile of 9a was reviewed in this work, the relevance of this compound in CB1R antagonist based drug discovery is confirmed