Past, Present and Future of the European Chemical Society (EuChemS).

50 years of EuChemS: In this Guest Editorial, F. Rutjes, EuChemS President-Elect, and P. Goya, EuChemS President, provide a brief overview of the history of the European Chemical Society and of what has been achieved over the past decades as well as an impression of the challenges that lie ahead.

Study of Meldrum's Acid Cyclization Reactions.

On the basis of the cyclization reactions reported by Danishefsky et al. of Meldrum's acid hydroxylethyl and anilinoethyl derivatives, the cyclization of the sulfamidomethylene and ureidomethylene derivatives was attempted without success. To understand the lack of reactivity of these compounds versus the successful cyclization of the ethyl derivatives, the corresponding mechanisms of reaction for both processes have been explored by means of MP2/6-311+G(d,p) calculations in an aqueous environment. The conformational analysis of all of these structures revealed that, while for the ethyl derivatives the minimum energy conformation corresponds to that of the cyclization initiating structure, for the methylene analogues the entrance channel conformations are substantially less stable than the energy minimum. Intramolecular hydrogen bonds were found in all of the energy minima as well as in the cyclization initiating conformations as determined by analysis of their electron density. The potential energy surfaces for the successful and unsuccessful cyclization processes were obtained at room temperature and 100 °C. Comparison of both processes allows rationalization that the lack of reactivity of the methylene derivatives can be thermodynamically explained based not only on the strength of the intramolecular hydrogen bond formed in their energy minima but also by the energy penalty needed to reach the entrance channel conformation and by the calculated energy barriers.

Novel antiobesity agents: synthesis and pharmacological evaluation of analogues of Rimonabant and of LH21.

Searching for novel antiobesity agents, a series of cannabinoid LH21 and of Rimonabant-fatty acid amide analogues have been prepared. Synthesis of pyrazoles 2a-2c was achieved by a two steps simple methodology via α,ß-unsaturated ketones. Carboxamides 8a-8h were obtained in good yields from esters 7a-7c by a one-pot procedure which takes place under mild conditions. New compounds have been evaluated in vivo as anorectic agents. Some of them showed interesting properties reducing food intake in rats by a mechanism which does not involve the endocannabinoid system.

Description of a bivalent cannabinoid ligand with hypophagic properties.

A series of bivalent cannabinoid ligands is proposed. The synthesis of double amides based on the rimonabant structure separated by an alkyl chain and the evaluation of their affinities for cannabinoid receptors are reported. The data of 4d confirmed that a bivalent structure is a suitable scaffold for CB1 cannabinoid receptor binding. The compound 4d was selected for in vitro and in vivo pharmacological evaluations. Moreover, intraperitoneal administration of 4d to food-deprived rats resulted in a dose-dependent inhibition of feeding that was maintained up to 240 min.

Antiobesity designed multiple ligands: Synthesis of pyrazole fatty acid amides and evaluation as hypophagic agents.

Searching for new antiobesity agents, a new series of fatty acid amide derivatives of 1,5-diarylpyrazole have been synthesized as dual peroxisome proliferator activated receptor alpha (PPARalpha)/cannabinoid receptor ligands. The compounds have been evaluated in vivo and in vitro as PPARalpha activators and as cannabinoids in two tests of the mouse tetrad. In vivo, food intake studies have been performed with all the compounds. No significant cannabinoid activity has been found but some compounds behaved as potent PPARalpha activators. Several compounds showed anorexigenic properties reducing food intake in rats.

Emerging strategies targeting CB2 cannabinoid receptor: Biased agonism and allosterism.

During these last years, the CB2 cannabinoid receptor has emerged as a potential anti-inflammatory target in diseases such as multiple sclerosis, amyotrophic lateral sclerosis, Huntington's disease, ischemic stroke, autoimmune diseases, osteoporosis, and cancer. However, the development of clinically useful CB2 agonists reveals to be very challenging. Allosterism and biased-signaling mechanisms at CB2 receptor may offer new avenues for the development of improved CB2 receptor-targeted therapies. Although there has been some exploration of CB1 receptor activation by new CB1 allosteric or biased-signaling ligands, the CB2 receptor is still at initial stages in this domain. In an effort to understand the molecular basis behind these pharmacological approaches, we have analyzed and summarized the structural data reported so far at CB2 receptor.

Novel sulfamide analogs of oleoylethanolamide showing in vivo satiety inducing actions and PPARalpha activation.

Long chain saturated and unsaturated alkyl sulfamide and propyl sulfamide derivatives, analogs of oleoylethanolamide, have been synthesized and evaluated in vivo and in vitro as peroxisome proliferator activated receptor alpha (PPARalpha) activators. Additionally, the anorexic effects of the new compounds have been studied in vivo in food-deprived rats. Among the active compounds N-octadecyl-N'-propylsulfamide (7) has been identified as a potent hypolipidemic compound, a potent feeding suppressant, and a concentration-dependent activator of PPARalpha.

Antiobesity effects of the novel in vivo neutral cannabinoid receptor antagonist 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-3-hexyl-1H-1,2,4-triazole--LH 21.

The present study evaluates the pharmacological profile of the new neutral cannabinoid CB1 receptor antagonist 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-3-hexyl-1H-1,2,4-triazole -LH-21- on feeding behavior and alcohol self-administration in rats, two behaviors inhibited by cannabinoid CB1 receptor antagonists. Administration of LH-21 (0.03, 0.3 and 3 mg/kg) to food-deprived rats resulted in a dose-dependent inhibition of feeding. Subchronic administration of LH-21 reduced food intake and body weight gain in obese Zucker rats. Acute effects on feeding were not associated with anxiety-like behaviors, or induction of complex motor behaviors such as grooming or scratching sequences, usually observed after central administration of cannabinoid receptor blockers with inverse agonist properties. LH-21 did not markedly reduce alcohol self-administration (30% reduction observed only at a high dose of 10 mg/kg). This pharmacological pattern partially overlaps that of the reference cannabinoid CB1 receptor antagonist N-piperidino-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methylpyrazole-3-carboxamide, SR141716A, (0.3, 1 and 3 mg/kg) that reduced feeding and alcohol self-administration with similar efficacy. In vitro analysis of blood-brain barrier permeability using a parallel artificial membrane permeation assay demonstrated that LH-21 has lower permeation through membranes than SR141716A. That was confirmed in vivo by studies showing lower potency of peripherally injected LH-21 when compared to SR141716A to antagonize motor depression induced by intracerebroventricular administration of the CB1 agonist CP55,940. The neutral antagonist profile and the lower penetration into the brain of LH-21 favour this class of antagonists with respect to reference inverse agonists for the treatment of obesity because they potentially will display reduced side effects.

Structural-activity relationship study on C-4 carbon atom of the CB1 antagonist SR141716: synthesis and pharmacological evaluation of 1,2,4-triazole-3-carboxamides.

A series of 1,2,4-triazole-3-carboxamides has been prepared from alkyl-1,2,4-triazole-3-carboxylates under mild conditions. The ability of these triazoles to displace [3H]-CP55940 from CB1 cannabinoid receptor was measured. However, they showed only poor to moderate binding affinities, indicating that substitution of the C-4 pyrazole atom of the CB1 reference compound SR141716 by a nitrogen atom results in loss of affinity. Further investigations for functionality indicated that the compound 6a exhibited significant cannabinoid antagonistic properties in the mouse vas deferens functional assay. This leads us to the conclusion that 6a binds at a different CB1 binding site or at a new cannabinoid receptor subtype.

Cannabinoid receptor 2 (CB2) agonists and antagonists: a patent update.

INTRODUCTION: Modulation of the CB2 receptor is an interesting approach for pain and inflammation, arthritis, addictions, neuroprotection, and cancer, among other possible therapeutic applications, and is devoid of central side effects. AREAS COVERED: This review highlights the novel scaffolds for CB2 ligands and the diverse therapeutic applications for CB2 modulators disclosed in patents published since 2012. EXPERT OPINION: Structural diversity of CB2 modulator scaffolds characterized the patent literature. Several CB2 agonists reached clinical Phase II for pain management and inflammation. Other therapeutic applications need to be explored such as neuroprotection and/or neurodegeneration.

Allosteric Modulators of the CB1 Cannabinoid Receptor: A Structural Update Review.

In 2005, the first evidence of an allosteric binding site at the CB1R was provided by the identification of three indoles of the company Organon that were allosteric enhancers of agonist binding affinity and, functionally, allosteric inhibitors of agonist activity. Since then, structure-activity relationships of indoles as CB1R modulators have been reported. Targeting the allosteric site on CB1R, new families structurally based on urea and on 3-phenyltropane analogs of cocaine have been discovered as CB1R-negative allosteric modulators (NAMs), respectively, by Prosidion and by the Research Triangle Park. Endogenous allosteric ligands of different nature have been identified more recently. Thus, the therapeutic neuroprotection application of lipoxin A4, an arachidonic acid derivative, as an allosteric enhancer of CB1R activity has been confirmed in vivo. It was also the case of the steroid hormone, pregnenolone, whose negative allosteric effects on Δ9-tetrahydrocannabinol (Δ9-THC) were reproduced in vivo in a behavioral tetrad model and in food intake and memory impairment assays. Curiously, the peroxisome proliferator-activated receptor-γ agonist fenofibrate or polypeptides such as pepcan-12 have been shown to act on the endocannabinoid system through CB1R allosteric modulation. The mechanistic bases of the effects of the phytocannabinoid cannabidiol (CBD) are still not fully explained. However, there is evidence that CBD behaves as an NAM of Δ9-THC- and 2-AG. Allosteric modulation at CB1R offers new opportunities for therapeutic applications. Therefore, further understanding of the chemical features required for allosteric modulation as well as their orthosteric probe dependence may broaden novel approaches for fine-tuning the signaling pathways of the CB1R.

Benzyl-1,2,4-triazoles as CB 1 Cannabinoid Receptor Ligands: Preparation and In Vitro Pharmacological Evaluation.

In a previous study, we have identified 3-alkyl-1,5-diaryl-1H-1,2,4-triazoles to be a novel class of cannabinoid type 1 receptor (CB1R) antagonists. In order to expand the number of cannabinoid ligands with a central 1,2,4-triazole scaffold, we have synthesized a novel series of 1-benzyl-1H-1,2,4-triazoles, and some of them were evaluated by CB1R radioligand binding assays. Compound 12a showed the most interesting pharmacological properties, possessing a CB1R affinity in the nanomolar range.

Identification of Novel GPR55 Modulators Using Cell-Impedance-Based Label-Free Technology.

The orphan G protein-coupled receptor GPR55 has been proposed as a novel receptor of the endocannabinoid system. However, the validity of this categorization is still under debate mainly because of the lack of potent and selective agonists and antagonists of GPR55. Binding assays are not yet available for GPR55 screening, and discrepancies in GPR55 mediated signaling pathways have been reported. In this context, we have designed and synthesized novel GPR55 ligands based on a chromenopyrazole scaffold. Appraisal of GPR55 activity was accomplished using a label-free cell-impedance-based assay in hGPR55-HEK293 cells. The real-time impedance responses provided an integrative assessment of the cellular consequence to GPR55 stimulation taking into account the different possible signaling pathways. Potent GPR55 partial agonists (14b, 18b, 19b, 20b, and 21-24) have been identified; one of them (14b) being selective versus classical cannabinoid receptors. Upon antagonist treatment, chromenopyrazoles 21-24 inhibited lysophosphatidylinositol (LPI) effect. One of these GPR55 antagonists (21) is fully selective versus classic cannabinoid receptors. Compared to LPI, the predicted physicochemical parameters of the new compounds suggest a clear pharmacokinetic improvement.

Chromenopyrazole, a Versatile Cannabinoid Scaffold with in Vivo Activity in a Model of Multiple Sclerosis.

A combination of molecular modeling and structure-activity relationship studies has been used to fine-tune CB2 selectivity in the chromenopyrazole ring, a versatile CB1/CB2 cannabinoid scaffold. Thus, a series of 36 new derivatives covering a wide range of structural diversity has been synthesized, and docking studies have been performed for some of them. Biological evaluation of the new compounds includes, among others, cannabinoid binding assays, functional studies, and surface plasmon resonance measurements. The most promising compound [43 (PM226)], a selective and potent CB2 agonist isoxazole derivative, was tested in the acute phase of Theiler's murine encephalomyelitis virus-induced demyelinating disease (TMEV-IDD), a well-established animal model of primary progressive multiple sclerosis. Compound 43 dampened neuroinflammation by reducing microglial activation in the TMEV.

Homology models of the cannabinoid CB1 and CB2 receptors. A docking analysis study.

The 3D models of both CB1 and CB2 human receptors have been established by homology modeling using as template the X-ray structure of bovine Rhodopsin (code pdb: 1F88) a G-protein-coupled receptor (GPCR). A recursive approach comprising sequence alignment and model building was used to build both models, followed by the refinement of non-conserved regions. The cannabinoid system has been studied by means of docking techniques, using the 3D models of both CB1 and CB2 and well known reference inverse agonist/antagonist compounds. An approach based on the flexibility of the structures has been used to model the receptor-ligand complexes. The structural effects of ligand binding were studied and analyzed on the basis of hydrogen bond interactions, and binding energy calculations. Potential interaction sites of the receptor were determined from analysis of the difference accessible surface area (DASA) study of the protein with and without ligand.

Selective, nontoxic CB(2) cannabinoid o-quinone with in vivo activity against triple-negative breast cancer.

Triple-negative breast cancer (TNBC) represents a subtype of breast cancer characterized by high aggressiveness. There is no current targeted therapy for these patients whose prognosis, as a group, is very poor. Here, we report the synthesis and evaluation of a potent antitumor agent in vivo for this type of breast cancer designed as a combination of quinone/cannabinoid pharmacophores. This new compound (10) has been selected from a series of chromenopyrazolediones with full selectivity for the nonpsychotropic CB2 cannabinoid receptor and with efficacy in inducing death of human TNBC cell lines. The dual concept quinone/cannabinoid was supported by the fact that compound 10 exerts antitumor effect by inducing cell apoptosis through activation of CB2 receptors and through oxidative stress. Notably, it did not show either cytotoxicity on noncancerous human mammary epithelial cells nor toxic effects in vivo, suggesting that it may be a new therapeutic tool for the management of TNBC.

Synthesis, pharmacological evaluation and docking studies of pyrrole structure-based CB2 receptor antagonists.

During the last years, there has been a continuous interest in the development of cannabinoid receptor ligands that may serve as therapeutic agents and/or as experimental tools. This prompted us to design and synthesize analogues of the CB2 receptor antagonist N-fenchyl-5-(4-chloro-3-methyl-phenyl)-1-(4-methyl-benzyl)-1H-pyrazole-3-carboxamide (SR144528). The structural modifications involved the bioisosteric replacement of the pyrazole ring by a pyrrole ring and variations on the amine carbamoyl substituents. Two of these compounds, the fenchyl pyrrole analogue 6 and the myrtanyl derivative 10, showed high affinity (Ki in the low nM range) and selectivity for the CB2 receptor and both resulted to be antagonists/inverse agonists in [(35)S]-GTPγS binding analysis and in an in vitro CB2 receptor bioassay. Cannabinoid receptor binding data of the series allowed identifying steric constraints within the CB2 binding pocket using a study of Van der Waals' volume maps. Glide docking studies revealed that all docked compounds bind in the same region of the CB2 receptor inactive state model.

Discovery of 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-3-hexyl-1h-1,2,4-triazole, a novel in vivo cannabinoid antagonist containing a 1,2,4-triazole motif.

A new series of 1,2,4-triazoles have been prepared and the evaluation of their cannabinoid properties have been carried out. Compound 8 showed cannabinoid silent antagonist activity in mouse vas deferens and guinea pig ileum preparations and in vivo assays (cannabinoid tetrad) in mouse. It did not have intrinsic activity in these bioassays, and therefore, it did not behave as a partial agonist or an inverse agonist.

Synthesis and opioid activity of new fentanyl analogs.

Three new fentanyl analogs (compounds 3-4-5) have been synthesized and evaluated for antinociceptive properties using the writhing test. The analgesic property of the active compound, N-[1-phenylpyrazol-3-yl]-N-[1-(2-phenethyl)-4-piperidyl)] propenamide (compound 4), was tested using the hot plate test in mice. Its opioid agonistic activity was characterized using three isolated tissues: guinea pig ileum, mouse vas deferens, and rabbit vas deferens. Compound 4 was as effective as fentanyl or morphine and it showed less antinociceptive potency than fentanyl but it was more potent than morphine. The duration of the antinociception was similar to that of fentanyl. This compound inhibited the electrically evoked contractions of myenteric plexus-longitudinal muscle strips of guinea pig ileum and of mouse vas deferens but not those of rabbit vas deferens. These effects could be reversed by micro selective antagonists (naloxone and/or CTOP) but not by the delta selective antagonist naltrindole, thus indicating that the compound acted as a micro opioid agonist. Finally, the binding data confirmed that compound 4 had high affinity and selectivity for the micro-receptor.

Enantioselective synthesis of PPAR (peroxisome proliferator-activated receptors) agonists and antagonists.

This review deals with stereoselective issues in PPAR ligands some of which are in clinical use for treating certain metabolic disorders. After a short introduction of these nuclear receptor and their agonists, some cases of enantioselective separations are reported. The main part concerns stereoselective synthesis first starting with asymmetric synthesis from chiral precursors followed by what we refer to as "true" enantioselective methods. Some examples are discussed in detail for each particular heading.