New class of potent ligands for the human peripheral cannabinoid receptor

doi:10.1016/0960-894X(96)00426-X

Bioorganic & Medicinal Chemistry Letters

Volume 6, Issue 19, 8 October 1996, Pages 2263-2268

https://doi.org/10.1016/0960-894X(96)00426-X Get rights and content

Abstract

A new class of potent ligand for the human peripheral cannabinoid (hCB₂) receptor is described. Two indole analogs 13 and 17 exhibited nanomolar potencies (K_i) with good selectivity for the hCB₂ receptor over the human central cannabinoid (hCB₁) receptor.

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Parkinson's disease (PD) is characterized by the progressive loss of dopaminergic (DAergic) neurons of the substantia nigra pars compacta (SNc) by neurodegeneration. Recent findings in animal models of PD propose tonic inhibition of the remaining DA neurons through GABA release from reactive glial cells. Movement dysfunctions could be ameliorated by promotion of activity in dormant DA cells. The endocannabinoid system (ECS) is extensively present in basal ganglia (BG) and is known as an indirect modulator of DAergic neurotransmission, thus drugs designed to target this system have shown promising therapeutic potential in PD patients. Interestingly, down/up-regulation of cannabinoid receptors (CBRs) varies across the different stages of PD, suggesting that some of the motor/ non-motor deficits may be related to changes in CBRs. Determination of the profile of changes of these receptors across the different stages of PD as well as their neural distribution within the BG could improve understanding of PD and identify pathways important in disease pathobiology. In this review, we focus on temporal and spatial alterations of CBRs during PD in the BG. At present, as inconclusive, but suggestive results have been obtained, future investigations should be conducted to extend preclinical studies examining CBRs changes within each stage in controlled clinical trials in order to determine the potential of targeting CBRs in management of PD.
Medicinal Chemistry approach, pharmacology and neuroprotective benefits of CB<inf>2</inf>R modulators in neurodegenerative diseases
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In the last decades, cannabinoid receptor 2 (CB₂R) has continued to receive attention as a key therapeutic target in neuroprotection. Indeed, several findings highlight the neuroprotective effects of CB₂R through suppression of both neuronal excitability and reactive microglia. Additionally, CB₂R seems to be a more promising target than cannabinoid receptor 1 (CB₁R) thanks to the lack of central side effects, its lower expression levels in the central nervous system (CNS), and its inducibility, since its expression enhances quickly in the brain following pathological conditions. This review aims to provide a thorough overview of the main natural and synthetic selective CB₂R modulators, their chemical classification and their potential therapeutic usefulness in neuroprotection, a crucial aspect for the treatment of neurodegenerative diseases.
7-Azaindolequinuclidinones (7-AIQD): A novel class of cannabinoid 1 (CB1) and cannabinoid 2 (CB2) receptor ligands
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A series of N-benzyl-7-azaindolequinuclidinone (7-AIQD) analogs have been synthesized and evaluated for affinity toward CB1 and CB2 cannabinoid receptors and identified as a novel class of cannabinoid receptor ligands. Structure–activity relationship (SAR) studies indicate that 7-AIQD analogs are dual CB1/CB2 receptor ligands exhibiting high potency with somewhat greater selectivity towards CB2 receptors compared to the previously reported indolequinuclidinone (IQD) analogs. Initial binding assays showed that 7-AIQD analogs 8b, 8d, 8f, 8g and 9b (1 μM) produced more that 50% displacement of the CB1/CB2 non-selective agonist CP-55,940 (0.1 nM). Furthermore, Ki values determined from full competition binding curves showed that analogs 8a, 8b and 8g exhibit high affinity (110, 115 and 23.7 nM, respectively) and moderate selectivity (26.3, 6.1 and 9.2-fold, respectively) for CB2 relative to CB1 receptors. Functional studies examining modulation of G-protein activity demonstrated that 8a acts as a neutral antagonist at CB1 and CB2 receptors, while 8b exhibits inverse agonist activity at these receptors. Analogs 8f and 8g exhibit different intrinsic activities, depending on the receptor examined. Molecular docking and binding free energy calculations for the most active compounds (8a, 8b, 8f, and 8g) were performed to better understand the CB2 receptor-selective mechanism at the atomic level. Compound 8g exhibited the highest predicted binding affinity at both CB1 and CB2 receptors, and all four compounds were shown to have higher predicted binding affinities with the CB2 receptor compared to their corresponding binding affinities with the CB1 receptor. Further structural optimization of 7-AIQD analogs may lead to the identification of potential clinical agents.
Identification and biochemical analyses of selective CB<inf>2</inf> agonists
2019, European Journal of Pharmacology
Citation Excerpt :
Another example is the cannabinoid CB2 receptor agonist GW405833. Its affinity for human the cannabinoid CB2 receptor ranges from 4 to 12 nM (Gallant et al., 1996; Valenzano et al., 2005), with selectivities for the human cannabinoid CB2 receptor over the human cannabinoid CB1 receptor ranging from 37- to 1217-fold (Valenzano et al., 2005; Yao et al., 2009). However, its anti-inflammatory effects are caused by the cannabinoid CB1 receptor pathway rather than the cannabinoid CB2 receptor one (Li et al., 2017).
Cannabinoid CB₁ and CB₂ receptors are activated by Δ⁹-tetrahydrocannabinol, a psychoactive component of marijuana. The cannabinoid CB₁ receptor is primarily located in the brain and is responsible for the psychoactive side effects, whereas the cannabinoid CB₂ receptor is located in immune cells and is an attractive target for immune-related maladies. We identify small molecules that selectively bind to the cannabinoid CB₂ receptor and can be further developed into therapeutics. The affinity of three molecules, ABK5, ABK6, and ABK7, to the cannabinoid CB₂ receptor was determined with radioligand competition binding. The potency of G-protein coupling was determined with GTPγS binding. The three compounds bound selectively to the cannabinoid CB₂ receptor_, and no binding to the cannabinoid CB₁ receptor was detected up to 10 μM. Immunoblotting studies show that the amount of ERK1/2 and MEK phosphorylation increased in a G_i/o-dependent manner. Furthermore, an immune cell line (Jurkat cells) was treated with ABK5, and as a result, inhibited cell proliferation. These three compounds are novel cannabinoid CB₂ receptor agonists and hold promise to be further developed to treat inflammation and the often-associated pain.
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The endogenous cannabinoids anandamide and 2-arachidonoylglycerol bind to the cannabinoid receptors of type 1 and 2. These receptors are also the binding sites for exogenous, both natural and synthetic, cannabinoids that are used for recreation purposes. Until recently, cannabinoids and cannabinoid receptors have attracted little interest among nephrologists; however, a full endocannabinoid system (ECS) is present in the kidney and it has recently emerged as an important player in the pathogenesis of diabetic nephropathy, drug nephrotoxicity, and progressive chronic kidney disease. This newly established role of the ECS in the kidney might have therapeutic relevance, as pharmacological modulation of the ECS has renoprotective effects in experimental animals, raising hope for future potential applications in humans. In addition, over the last years, there has been a number of reported cases of acute kidney injury (AKI) associated with the use of synthetic cannabinoids that appear to have higher potency and rate of toxicity than natural Cannabis. This poorly recognized cause of renal injury should be considered in the differential diagnosis of AKI, particularly in young people. In this review we provide an overview of preclinical evidence indicating a role of the ECS in renal disease and discuss potential future therapeutic applications. Moreover, we give a critical update of synthetic cannabinoid-induced AKI.

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New class of potent ligands for the human peripheral cannabinoid receptor

Abstract

Tetrahedron

Nature

Nature

Biochem. J.

Chem. Abstr.

Pharmacol. Rev.

Cannabinoids as Therapeutic Agents

Pharma. Rev.

JAMA