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.

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.

Novel approaches and current challenges with targeting the endocannabinoid system.

Introduction: The pathophysiological relevance of the endocannabinoid system has been widely demonstrated in a variety of diseases including cancer, neurological disorders, and metabolic issues. Therefore, targeting the receptors and the endogenous machinery involved in this system can provide a successful therapeutic outcome. Ligands targeting the canonical cannabinoid receptors, CB and CB, along with inhibitors of the endocannabinoid enzymes have been thoroughly studied in diverse disease models.

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.

Increased expression of cannabinoid CB and serotonin 5-HT heteroreceptor complexes in a model of newborn hypoxic-ischemic brain damage.

Preclinical work shows cannabidiol as a promising drug to manage neonatal hypoxic-ischemic brain damage (NHIBD). The molecular mechanism is not well defined but the beneficial effects of this phytocannabinoid are blocked by antagonists of both cannabinoid CB (CBR) and serotonin 5-HT (5-HT1AR) receptors that, in addition, may form heteromers in a heterologous expression system. Using bioluminescence energy transfer, we have shown a direct interaction of the two receptors that leads to a particular signaling in a heterologous system.

Cannabidiol skews biased agonism at cannabinoid CB and CB receptors with smaller effect in CB-CB 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.

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

During these last years, the CB 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 CB agonists reveals to be very challenging. Allosterism and biased-signaling mechanisms at CB receptor may offer new avenues for the development of improved CB receptor-targeted therapies.

New Methods for the Synthesis of Cannabidiol Derivatives.

Cannabidiol (CBD) is one of the most abundant components isolated from Cannabis sativa. However, CBD is a nonpsychotropic phytocannabinoid. In the last decade, there has been a growing interest in its therapeutic effects.

An Overview on Medicinal Chemistry of Synthetic and Natural Derivatives of Cannabidiol.

Cannabidiol (CBD) has been traditionally used in -based preparation, however historically, it has received far less interest as a single drug than the other components of . Currently, CBD generates considerable interest due to its beneficial neuroprotective, antiepileptic, anxiolytic, antipsychotic, and anti-inflammatory properties. Therefore, the CBD scaffold becomes of increasing interest for medicinal chemists.

New pyridazinone-4-carboxamides as new cannabinoid receptor type-2 inverse agonists: Synthesis, pharmacological data and molecular docking.

In the last few years, cannabinoid type-2 receptor (CBR) selective ligands have shown a great potential as novel therapeutic drugs in several diseases. With the aim of discovering new selective cannabinoid ligands, a series of pyridazinone-4-carboxamides was designed and synthesized, and the new derivatives tested for their affinity toward the hCBR and hCBR. The 6-(4-chloro-3-methylphenyl)-2-(4-fluorobenzyl)-N-(cis-4-methylcyclohexyl)-3-oxo-2,3-dihydropyridazine-4-carboxamide (9) displayed high CB-affinity (KCB = 2.

Targeting Cannabinoid CB2 Receptors in the Central Nervous System. Medicinal Chemistry Approaches with Focus on Neurodegenerative Disorders.

Endocannabinoids activate two types of specific G-protein-coupled receptors (GPCRs), namely cannabinoid CB1 and CB2. Contrary to the psychotropic actions of agonists of CB1 receptors, and serious side effects of the selective antagonists of this receptor, drugs acting on CB2 receptors appear as promising drugs to combat CNS diseases (Parkinson's disease, Huntington's chorea, cerebellar ataxia, amyotrohic lateral sclerosis). Differential localization of CB2 receptors in neural cell types and upregulation in neuroinflammation are keys to understand the therapeutic potential in inter alia diseases that imply progressive neurodegeneration.

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.

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.

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.