Publications by authors named "Nadine Jagerovic"

Article Synopsis
  • Class A G protein-coupled receptors (GPCRs) are important for cell signaling and are major drug targets, yet over 60% of them remain untapped for therapeutic use.
  • Traditional GPCR drugs often have adverse effects, but biased signaling offers a new approach for discovering safer therapeutics by targeting specific receptor conformations.
  • The review outlines the landscape of GPCR-biased modulators, highlighting recent advancements, therapeutic relevance, and the variations in understanding their biological effects across different GPCR families.
View Article and Find Full Text PDF
Article Synopsis
  • G protein-coupled receptors (GPCRs) are dynamic structures that can exist in different forms and are influenced by ligand binding, balancing between monomers and oligomers.
  • A new bivalent ligand, which contains two linked pharmacophore units, can affect the behavior of the cannabinoid CB receptor (CBR) by binding to both parts of its dimer form.
  • This binding leads to increased signaling potency and better recruitment of β-arrestin, suggesting that manipulating receptor dimerization could enhance therapeutic effects for treatments involving cannabinoid receptors.
View Article and Find Full Text PDF

The Cannabinoid 2 Receptor (CB2R) has been found to provide immunological modulation in different cell types. More recently, detection of CB2R in the cerebral endothelium suggests a possible role in the resolution of inflammation at the level of the blood-brain-barrier (BBB). Here, the notion that CB2R upregulation in brain endothelial cells could be exploited to promote vascular protection and BBB integrity was evaluated.

View Article and Find Full Text PDF

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.

View Article and Find Full Text PDF

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.

View Article and Find Full Text PDF

Both metabotropic (CBRs) and ionotropic cannabinoid receptors (ICRs) have implications in a range of neurological disorders. The metabotropic canonical CBRs CB1 and CB2 are highly implicated in these pathological events. However, selective targeting at CB2 versus CB1 offers optimized pharmacology due to the absence of psychoactive outcomes.

View Article and Find Full Text PDF

The classical terms agonists and antagonists for G protein coupled receptors (GPCRs) have often become misleading. Even the biased agonism concept does not describe all the possibilities already demonstrated for GPCRs. The cannabinoid CB receptor (CBR) emerged as a promising target for a variety of diseases.

View Article and Find Full Text PDF

Cannabinoids act as pleiotropic compounds exerting, among others, a broad-spectrum of neuroprotective effects. These effects have been investigated in the last years in different preclinical models of neurodegeneration, with the cannabinoid type-1 (CB) and type-2 (CB) receptors concentrating an important part of this research. However, the issue has also been extended to additional targets that are also active for cannabinoids, such as the orphan G-protein receptor 55 (GPR55).

View Article and Find Full Text PDF

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.

View Article and Find Full Text PDF

The non-psychoactive component of Cannabis Sativa, cannabidiol (CBD), has centered the attention of a large body of research in the last years. Recent clinical trials have led to the FDA approval of CBD for the treatment of children with drug-resistant epilepsy. Even though it is not yet in clinical phases, its use in sleep-wake pathological alterations has been widely demonstrated.

View Article and Find Full Text PDF

Cannabinoids have shown to exert their therapeutic actions through a variety of targets. These include not only the canonical cannabinoid receptors CBR and CBR but also related orphan G protein-coupled receptors (GPCRs), ligand-gated ion channels, transient receptor potential (TRP) channels, metabolic enzymes, and nuclear receptors. In this review, we aim to summarize reported compounds exhibiting their therapeutic effects upon the modulation of CBR and/or CBR and the nuclear peroxisome proliferator-activated receptors (PPARs).

View Article and Find Full Text PDF

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.

View Article and Find Full Text PDF

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 CB receptor. These compounds selectively target CB versus CB receptors.

View Article and Find Full Text PDF

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.

View Article and Find Full Text PDF

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.

View Article and Find Full Text PDF

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.

View Article and Find Full Text PDF

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.

View Article and Find Full Text PDF

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.

View Article and Find Full Text PDF

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.

View Article and Find Full Text PDF

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.

View Article and Find Full Text PDF

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.

View Article and Find Full Text PDF

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.

View Article and Find Full Text PDF

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.

View Article and Find Full Text PDF

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.

View Article and Find Full Text PDF

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.

View Article and Find Full Text PDF