The Plant Derived 3-3'-Diindolylmethane (DIM) Behaves as CB Receptor Agonist in Prostate Cancer Cellular Models.

3-3'-Diindolylmethane (DIM) is a biologically active dimer derived from the endogenous conversion of indole-3-carbinol (I3C), a naturally occurring glucosinolate found in many cruciferous vegetables (i.e., ).

Design, synthesis and biological evaluation of novel orthosteric-allosteric ligands of the cannabinoid receptor type 2 (CBR).

It is well known that G protein-coupled receptors (GPCRs) assume multiple active states. Orthosteric ligands and/or allosteric modulators can preferentially stabilize specific conformations, giving rise to pathway-biased signaling. One of the most promising strategies to expand the repertoire of signaling-selective GPCR activators consists of dualsteric agents, which are hybrid compounds consisting of orthosteric and allosteric pharmacophoric units.

Cyclic AMP Assay Using Human Cannabinoid CB Receptor-Transfected Cells.

The cyclic AMP assay is a functional assay that is commonly used to determine the pharmacological behavior (agonists, antagonists, and inverse agonists) of G-protein coupled receptor ligands. Here, we describe the cyclic AMP assay that is carried out with commercially available nonradioligand ready-to-use kits and CHO (Chinese Hamster Ovarian) cells stably transfected with the human cannabinoid CB receptor.

Displacement Binding Assay Using Human Cannabinoid CB Receptor-Transfected Cells.

Displacement binding assays are nonfunctional assays mostly used with the aim of determining whether a certain compound (plant-derived or synthetic) can bind to a specific receptor with high affinity. Here, we describe the displacement binding assay that is carried out with a radioligand and CHO (Chinese Hamster Ovarian) cells stably transfected with the human cannabinoid CB receptor.

Design, Synthesis, and Biological Activity of New CB2 Receptor Ligands: from Orthosteric and Allosteric Modulators to Dualsteric/Bitopic Ligands.

The design of dualsteric/bitopic agents as single chemical entities able to simultaneously interact with both the orthosteric and an allosteric binding site represents a novel approach in medicinal chemistry. Biased dualsteric/bitopic agents could enhance certain signaling pathways while diminishing the others that cause unwanted side effects. We have designed, synthesized, and functionally characterized the first CB2R heterobivalent bitopic ligands.

Motor-like Tics are Mediated by CB Cannabinoid Receptor-dependent and Independent Mechanisms Associated with Age and Sex.

Δ-Tetrahydrocannabinol (Δ-THC) inhibits tics in individuals with Tourette syndrome (TS). Δ-THC has similar affinities for CB/CB cannabinoid receptors. However, the effect of HU-308, a selective CB receptor agonist, on repetitive behaviors has not been investigated.

Osteogenic growth peptide is a potent anti-inflammatory and bone preserving hormone via cannabinoid receptor type 2.

The endocannabinoid system consists mainly of 2-arachidonoylglycerol and anandamide, as well as cannabinoid receptor type 1 and type 2 (CB2). Based on previous studies, we hypothesized that a circulating peptide previously identified as osteogenic growth peptide (OGP) maintains a bone-protective CB2 tone. We tested OGP activity in mouse models and cells, and in human osteoblasts.

Synthesis and In Vitro Characterization of Selective Cannabinoid CB2 Receptor Agonists: Biological Evaluation against Neuroblastoma Cancer Cells.

1,8-naphthyridine-3-carboxamide structures were previously identified as a promising scaffold from which to obtain CB2R agonists with anticancer and anti-inflammatory activity. This work describes the synthesis and functional characterization of new 1,8-naphthyridin-2(1)-one-3-carboxamides with high affinity and selectivity for CB2R. The new compounds were able to pharmacologically modulate the cAMP response without modulating CB2R-dependent β-arrestin2 recruitment.

Design, synthesis, and pharmacological profiling of cannabinoid 1 receptor allosteric modulators: Preclinical efficacy of C2-group GAT211 congeners for reducing intraocular pressure.

Allosteric modulators of cannabinoid 1 receptor (CB1R) show translational promise over orthosteric ligands due to their potential to elicit therapeutic benefit without cannabimimetic side effects. The prototypic 2-phenylindole CB1R allosteric modulator, GAT211 (1), demonstrates preclinical efficacy in various disease models. The limited systematic structure-activity relationship (SAR) data at the C2 position of the indole ring within GAT211 invites the opportunity for further modifications to improve GAT211's pharmacological profile while serving to amplify and variegate this library of therapeutically attractive agents.

Assessing the treatment of cannabidiolic acid methyl ester: a stable synthetic analogue of cannabidiolic acid on c-Fos and NeuN expression in the hypothalamus of rats.

Background: Cannabidiol (CBD), the non-psychotropic compound from Cannabis sativa, shows positive results on controlling several health disturbances; however, comparable data regarding additional chemical from C. sativa, such as cannabidiolic acid (CBDA), is scarce due to its instability. To address this limitation, a stable CBDA analogue, CBDA methyl ester (HU-580), was synthetized and showed CBDA-like effects.

Therapeutic Potential of Cannabidiol, Cannabidiolic Acid, and Cannabidiolic Acid Methyl Ester as Treatments for Nausea and Vomiting.

Nausea and vomiting are the most distressing symptoms reported by oncology patients undergoing anticancer treatment. With the currently available treatments, vomiting and especially nausea remain problematic, highlighting the need for alternative treatments. Here we review and evidence for the effectiveness of the nonpsychoactive cannabinoid cannabidiol (CBD) in managing nausea and vomiting.

Discovery of a Biased Allosteric Modulator for Cannabinoid 1 Receptor: Preclinical Anti-Glaucoma Efficacy.

We apply the magic methyl effect to improve the potency/efficacy of GAT211, the prototypic 2-phenylindole-based cannabinoid type-1 receptor (CB1R) agonist-positive allosteric modulator (ago-PAM). Introducing a methyl group at the α-position of nitro group generated two diastereomers, the greater potency and efficacy of , (±)- vs , (±)- constitutes the first demonstration of diastereoselective CB1R-allosteric modulator interaction. Of the (±)- enantiomers, (-)-(,)- evidenced improved potency over GAT211 as a CB1R ago-PAM, whereas (+)-(,)- was a CB1R allosteric agonist biased toward G protein- vs β-arrestin1/2-dependent signaling.

Variously substituted 2-oxopyridine derivatives: Extending the structure-activity relationships for allosteric modulation of the cannabinoid CB2 receptor.

We previously reported the 2-oxopyridine-3-carboxamide derivative EC21a as the first small synthetic CB2R positive allosteric modulator which displayed antinociceptive activity in vivo in an experimental mouse model of neuropathic pain. Herein, we extended the structure-activity relationships of EC21a through structural modifications regarding the p-fluoro benzyl moiety at position 1 and the amide group in position 3 of the central core. The characterization in vitro was assessed through radioligand binding experiments and functional assays (GTPγS, cAMP, βarrestin2).

Effects on the Post-translational Modification of H3K4Me3, H3K9ac, H3K9Me2, H3K27Me3, and H3K36Me2 Levels in Cerebral Cortex, Hypothalamus and Pons of Rats after a Systemic Administration of Cannabidiol: A Preliminary Study.

Background: Cannabidiol (CBD), a non-psychotropic constituent of Cannabis sativa, has shown therapeutic promises by modulating several pathological conditions, including pain, epilepsy autism, among others. However, the molecular mechanism of action of CBD remains unknown and recent data suggest the engagement on CBD´s effects of nuclear elements, such as histone activity.

Aim: This study assessed the changes in the post-translational modification (PTM) on the histones H3K4Me3, H3K9ac, H3K9Me2, H3K27Me3, and H3K36Me2 in several brain regions of rats after the administration of CBD (20 mg/Kg/i.

PSNCBAM-1 analogs: Structural evolutions and allosteric properties at cannabinoid CB1 receptor.

Allosteric modulation of the CB1Rs could represent an alternative strategy for the treatment of diseases in which these receptors are involved, without the undesirable effects associated with their orthosteric stimulation. PSNCBAM-1 is a reference diaryl urea derivative that positively affects the binding affinity of orthosteric ligands (PAM) and negatively affects the functional activity of orthosteric ligands (NAM) at CB1Rs. In this work we reported the design, synthesis and biological evaluation of three different series of compounds, derived from structural modifications of PSNCBAM-1 and its analogs reported in the recent literature.

Synthetic bioactive olivetol-related amides: The influence of the phenolic group in cannabinoid receptor activity.

Focusing on the importance of the free phenolic hydroxyl moiety, a family of 23 alkylresorcinol-based compounds were developed and evaluated for their cannabinoid receptor binding properties. The non-symmetrical hexylresorcinol derivative 29 turned out to be a CB2-selective competitive antagonist/inverse agonist endowed with good potency. Both the olivetol- and 5-(2-methyloctan-2-yl)resorcinol-based derivatives 23 and 24 exhibited a significant antinociceptive activity.

Sleep and neurochemical modulation by cannabidiolic acid methyl ester in rats.

Cannabidiolic acid methyl ester (HU-580) is a more stable compound than cannabidiolic acid (CBDA) which has been shown to be effective in reducing nausea, anxiety, depression behaviors in animal models. Here we extend the investigation of this compound to determine its effect on the sleep-wake cycle in male Wistar rats. HU-580 dose-dependently (0.

Application of Fluorine- and Nitrogen-Walk Approaches: Defining the Structural and Functional Diversity of 2-Phenylindole Class of Cannabinoid 1 Receptor Positive Allosteric Modulators.

Cannabinoid 1 receptor (CB1R) allosteric ligands hold a far-reaching therapeutic promise. We report the application of fluoro- and nitrogen-walk approaches to enhance the drug-like properties of GAT211, a prototype CB1R allosteric agonist-positive allosteric modulator (ago-PAM). Several analogs exhibited improved functional potency (cAMP, β-arrestin 2), metabolic stability, and aqueous solubility.

Indomethacin Enhances Type 1 Cannabinoid Receptor Signaling.

In addition to its known actions as a non-selective cyclooxygenase (COX) 1 and 2 inhibitor, we hypothesized that indomethacin can act as an allosteric modulator of the type 1 cannabinoid receptor (CB1R) because of its shared structural features with the known allosteric modulators of CB1R. Indomethacin enhanced the binding of [H]CP55940 to hCB1R and enhanced AEA-dependent [S]GTPγS binding to hCB1R in Chinese hamster ovary (CHO) cell membranes. Indomethacin (1 μM) also enhanced CP55940-dependent βarrestin1 recruitment, cAMP inhibition, ERK1/2 and PLCβ3 phosphorylation in HEK293A cells expressing hCB1R, but not in cells expressing hCB2R.