Antitumor Cannabinoid Chemotypes: Structural Insights

Cannabis has long been known to limit or prevent nausea and vomiting, lack of appetite, and pain. For this reason, cannabinoids have been successfully used in the treatment of some of the unwanted side effects caused by cancer chemotherapy. Besides their palliative effects, research from the past two decades has demonstrated their promising potential as antitumor agents in a wide variety of tumors. Cannabinoids of endogenous, phytogenic, and synthetic nature have been shown to impact the proliferation of cancer through the modulation of different proteins involved in the endocannabinoid system such as the G protein–coupled receptors CB1, CB2, and GRP55, the ionotropic receptor TRPV1, or the fatty acid amide hydrolase (FAAH). In this article, we aim to structurally classify the antitumor cannabinoid chemotypes described so far according to their targets and types of cancer. In a drug discovery approach, their in silico pharmacokinetic profile has been evaluated in order to identify appropriate drug-like profiles, which should be taken into account for further progress toward the clinic. This analysis may provide structural insights into the selection of specific cannabinoid scaffolds for the development of antitumor drugs for the treatment of particular types of cancer

Derivados de cromenopirazoles como ligandos de receptores de cannabinoides

Derivados de cromenopirazoles como ligandos de receptores de cannabinoides. Compuestos derivados de cromenopirazoles que son ligandos de receptores de cannabinoides, su uso para la fabricación de un medicamento, uso de este medicamento para el tratamiento y/o la prevención de trastornos asociados a los receptores de cannabinoides, uso de dicho compuesto como reactivo en ensayos biológicos relacionados con receptores de cannabinoides y procedimiento de obtención de los mismos.Peer reviewedConsejo Superior de Investigaciones Científicas (España), Universidad Complutense de MadridA1 Solicitud de patente con informe sobre el estado de la técnic

The Chromenopyrazole Scaffold in the Modulation of the Endocannabinoid System: A Broad Therapeutic Prospect

The endogenous cannabinoid system (ECS) has been recognized as one of the most important neuromodulatory systems. This system plays a crucial role in the regulation of numerous pathophysiological conditions such as pain, cancer, or neurodegeneration. Despite the vast effort focused on the development of drugs targeting the ECS, thus far, the clinical use of synthetic and phytogenic cannabinoids has been limited to pain, emesis and appetite due to their undesirable psychoactive properties. Therefore, novel strategies to therapeutically exploit the cannabinoids need to be developed to overcome these side-effects. Moreover, novel chemical tools to study the role of possible additional cannabinoid missing receptors, such as GPR55, need to be addressed to fully unravel the pharmacology of this complex system.In this scenario, the chromenopyrazole scaffold was recently discovered as a privileged structure in drug discovery targeting the ECS. In this review, the development of novel modulators of the ECS based on the chromenopyrazole scaffold will be thoroughly discussed. Pharmacological avenues for this novel chemotype, as well as future perspectives will be analyzed

LH-21, a CB1 antagonist, reduces hepatotoxic damage produced by paracetamol overdose in a mice model.

Drug-induced liver injury (DILI) is one of the main causes of hepatic acute failure. Paracetamol can cause it when is ingested in excessive doses, leading to the depletion of the antioxidant mechanisms of the hepatocytes and a series of processes that conclude with cell death. One of the altered metabolic pathways is the endocannabinoid system (ECS), which has become a very interesting target to alleviate these events due to its involvement in inflammatory processes. For this reason, the triazole-derived compound LH-21, a cannabinoid receptor Cb1 antagonist, was used for the treatment of DILI in 8-week-old male C57BL/6 mice. In the present study, fasting mice were subjected to an oral overdose of paracetamol (300 mg/kg) and treated 2 hours later with 3 mg/kg of LH-21. After 24 hours, the animals were sacrificed and the livers were collected to determine the hepatic levels of metabolites related to antioxidant mechanisms, the expression of proteins involved in the generation of cellular damage and the transcription grade of the different components of the ECS. The observed results showed that LH-21 treatment raises GSH levels and total antioxidant capacity, in addition to reducing malondialdehyde values. Furthermore, the phosphorylation degree of Jnk and Stat3, as well as the activation status of Casp3, diminished. Regarding the ECS, the expression of Ppara, Cnr1, Cnr2 and Gpr55 did return to normal levels. This suggests that LH-21 effectively blocks the Cb1 activity, allowing the correct function of Ppar-α that promotes a cellular anti-inflammatory state and the relief of the symptoms produced by DILI. These results exhibit a promising perspective for the prevention or treatment of some toxic effects of paracetamol overdose with LH-21. Nevertheless, these findings are a first step to continue studying the involvement of the ECS in this type of liver disease and investigating the effectiveness of this Cb1 antagonist against the pathophysiology of DILI.Universidad de Málaga. Campus de Excelencia Internacional Andalucía Tech

The structure of the agrochemical fungicidal 4-Chloro-3-(3,5-dichloropheny)-1H-pyrazole, RPA 406194 and related compounds

The difficulties to obtain convenient monocrystals of the important fungicide RPA 406194 have been overcome by a combination of solid state 13C NMR, X-ray powder diffraction and molecular modeling. The compound, a 3-aryl tautomer, crystallizes forming infinite chains of molecules bonded by N–H· · ·N hydrogen bonds, leading to needle-shaped crystals. The tautomerism (equilibrium constant and energy barrier) of this compound in solution has been studied

Discovery of Homobivalent Bitopic Ligands of the Cannabinoid CB2 Receptor**

Single chemical entities with potential to simultaneously interact with two binding sites are emerging strategies in medicinal chemistry. We have designed, synthesized and functionally characterized the first bitopic ligands for the CB2 receptor. These compounds selectively target CB2 versus CB1 receptors. Their binding mode was studied by molecular dynamic simulations and site-directed mutagenesis

Cannabidiol skews biased agonism at cannabinoid CB1 and CB2 receptors with smaller effect in CB1-CB2 heteroreceptor complexes

Currently, biased agonism is at the center stage of drug development approaches. We analyzed effects of a battery of cannabinoids plus/minus cannabidiol (CBD) in four functional parameters (cAMP levels, phosphorylation of extracellular signal–regulated kinases (ERK1/2), β-arrestin recruitment and label-free/DMR) in HEK-293T cells expressing cannabinoid receptors, CB or CB, or CB-CB heteroreceptor complexes. In all cases two natural agonists plus two selective synthetic agonists were used. Furthermore, the effect of cannabidiol, at a dose (100 nM) that does not allow significant binding to the orthosteric center of either receptor, was measured. From the huge amount of generated data, we would like to highlight that the two psychotropic molecules (Δ-tetrahydrocannabinol/THC and CP-55940) showed similar bias in CBR and that the bias of THC was particularly relevant toward MAPK pathway. Furthermore, THC did not activate the G protein coupled to CBR. Interestingly, the biased agonism was reduced when assays were performed in cells expressing the two receptors, thus suggesting that the heteromer allows less functional selectivity. In terms of cannabidiol action, the phytocannabinoid altered the functional responses, likely by allosteric means, and modified potency, agonist IC/EC values and biased agonism in qualitative and/or quantitative different ways depending on the agonist. The effect of cannabidiol on anandamide actions on both cannabinoid receptors was particularly noteworthy as was significantly different from that of other compounds. Results are a compendium of data on biased agonism on cannabinoid receptors in the absence and presence of cannabidiol. In addition, for the first time, GPCR biased agonism is characterized in an heteromeric context.This work was partially supported by grants from the Spanish Ministry of Economy and Competitiveness (Ref. no. BFU2015-64405-R and SAF2017-84117-R; they may include FEDER funds) and by grant 201413-30 from: Fundació la Marató de TV3Peer Reviewe

Administration of Linoleoylethanolamide Reduced Weight Gain, Dyslipidemia, and Inflammation Associated with High-Fat-Diet-Induced Obesity

Acylethanolamides (NAEs) are bioactive lipids derived from diet fatty acids that modulate important homeostatic functions, including appetite, fatty acid synthesis, mitochondrial respiration, inflammation, and nociception. Among the naturally circulating NAEs, the pharmacology of those derived from either arachidonic acid (Anandamide), oleic acid (OEA), and palmitic acid (PEA) have been extensively characterized in diet-induced obesity. For the present work, we extended those studies to linoleoylethanolamide (LEA), one of the most abundant NAEs found not only in plasma and body tissues but also in foods such as cereals. In our initial study, circulating concentrations of LEA were found to be elevated in overweight humans (body mass index (BMI, Kg/m) > 25) recruited from a representative population from the south of Spain, together with AEA and the endocannabinoid 2-Arachidonoyl glycerol (2-AG). In this population, LEA concentrations correlated with the circulating levels of cholesterol and triglycerides. In order to gain insight into the pharmacology of LEA, we administered it for 14 days (10 mg/kg i.p. daily) to obese male Sprague Dawley rats receiving a cafeteria diet or a standard chow diet for 12 consecutive weeks. LEA treatment resulted in weight loss and a reduction in circulating triglycerides, cholesterol, and inflammatory markers such as Il-6 and Tnf-alpha. In addition, LEA reduced plasma transaminases and enhanced acetyl-CoA-oxidase (Acox) and Uncoupling protein-2 (Ucp2) expression in the liver of the HFD-fed animals. Although the liver steatosis induced by the HFD was not reversed by LEA, the overall data suggest that LEA contributes to the homeostatic signals set in place in response to diet-induced obesity, potentially contributing with OEA to improve lipid metabolism after high fat intake. The anti-inflammatory response associated with its administration suggests its potential for use as a nutrient supplement in non-alcoholic steatohepatitis.Juan Decara holds a “Miguel Servet” (CP21/00021) research contract from the Ministerio de Ciencia e Innovación, Instituto de Salud Carlos III (ISCIII), cofunded by European Social Fund, “Investing in your future”, Gobierno de España. The present work was funded by Instituto de Salud Carlos III (ISCIII), Ministerio de Ciencia e Innovación; European Regional Development Funds Euro- pean Union (ERDF-EU) grants “Proyectos de Investigación en Salud” PI19/01577 and PI22/00427; Proyectos de investigación en salud (PI-0139-2018) Consejería de Salud y Familias, Junta de An- dalucía, Proyecto de Investigación en Salud; grant for international postdoctoral stay “Jose Castillejo” Program (Grant CAS15/00257), Ministerio de Educación Cultura y Deporte, Gobierno de España. The funders had no role in the design of the study; in the collection, analysis, and interpretation of data; in the writing of the report; and in the decision to submit the paper for publication

Thienopyrimidine Derivatives as GPR55 Receptor Antagonists: Insight into Structure-Activity Relationship

GPR55 is an orphan G-protein coupled receptor involved in various pathophysiological conditions. However, there are only a few noncannabinoid GPR55 ligands reported so far. The lack of potent and selective GPR55 ligands precludes a deep exploration of this receptor. The studies presented here focused on a thienopyrimidine scaffold based on the GPR55 antagonist ML192, previously discovered by high-throughput screening. The GPR55 activities of the new synthesized compounds were assessed using β-arrestin recruitment assays in Chinese hamster ovary cells overexpressing human GPR55. Some derivatives were identified as GPR55 antagonists with functional efficacy and selectivity versus CB1 and CB2 cannabinoid receptors.M.E.A., P.H.R., and N.J. are supported by National Institutes of Health grant R01 DA0455698. M.E.A. and P.Z. thank the financial support NIH P30 DA013429. P.M. 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. P.M. acknowledges the Comunidad de Madrid (CM) programme “Atraccion de Talento” number 2018-T2/BMD-10819 and “Juan de la Cierva Incorporación Programme-MICIU” (IJC 2019-042182-I

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