Ligand-based virtual screening identifies a family of selective cannabinoid receptor 2 agonists

Gianella-Borradori, Matteo; Christou, Ivy; Bataille, Carole J. R.; Cross, Rebecca; Wynne, Graham M.; Greaves, David R.; Russell, Angela J.

doi:10.1016/j.bmc.2014.11.002

Cited by 20 publications

(14 citation statements)

References 78 publications

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“…Figure 1A shows that the classical, widely used and potent CB 2 agonist JWH133 significantly induced PEC migration (P < 0.001 compared to vehicle alone). In contrast, our own novel and selective CB 2 agonist, DIAS2 30 , did not induce PEC chemotaxis regardless of the concentration used. DIAS2 had no effect on cell viability at all of the concentrations used (data not shown), ruling out toxicity as an explanation for the absence of migration.…”

Section: Resultscontrasting

confidence: 56%

Primary Macrophage Chemotaxis Induced by Cannabinoid Receptor 2 Agonists Occurs Independently of the CB2 Receptor

Taylor

Christou

Kapellos

et al. 2015

Sci Rep

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Activation of CB2 has been demonstrated to induce directed immune cell migration. However, the ability of CB2 to act as a chemoattractant receptor in macrophages remains largely unexplored. Using a real-time chemotaxis assay and a panel of chemically diverse and widely used CB2 agonists, we set out to examine whether CB2 modulates primary murine macrophage chemotaxis. We report that of 12 agonists tested, only JWH133, HU308, L-759,656 and L-759,633 acted as macrophage chemoattractants. Surprisingly, neither pharmacological inhibition nor genetic ablation of CB2 had any effect on CB2 agonist-induced macrophage chemotaxis. As chemotaxis was pertussis toxin sensitive in both WT and CB2-/- macrophages, we concluded that a non-CB1/CB2, Gi/o-coupled GPCR must be responsible for CB2 agonist-induced macrophage migration. The obvious candidate receptors GPR18 and GPR55 could not mediate JWH133 or HU308-induced cytoskeletal rearrangement or JWH133-induced β-arrestin recruitment in cells transfected with either receptor, demonstrating that neither are the unidentified GPCR. Taken together our results conclusively demonstrate that CB2 is not a chemoattractant receptor for murine macrophages. Furthermore we show for the first time that JWH133, HU308, L-759,656 and L-759,633 have off-target effects of functional consequence in primary cells and we believe that our findings have wide ranging implications for the entire cannabinoid field.

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Section: Resultscontrasting

confidence: 56%

Primary Macrophage Chemotaxis Induced by Cannabinoid Receptor 2 Agonists Occurs Independently of the CB2 Receptor

Taylor

Christou

Kapellos

et al. 2015

Sci Rep

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“…Nevertheless our laboratories have had some limited success in identifying in vitro activators of creatine uptake by using a ligand-based virtual screening method to cherry pick compounds from our in-house 25,000-member screening collection. These types of in silico screening approaches are increasingly employed within discovery programmes, particularly where the structure of the biological target is unknown, or no reliable models are available, and can yield improved hit rates compared to a screen of a randomly diverse compound collection (For a review see: [89, 90]). We use a mouse fibroblast cell line that stably overexpresses the CrT and incubate candidate compounds in 24-well plates spiked with 14 C-creatine.…”

Section: The Creatine Transporter As a Pharmacological Targetmentioning

confidence: 99%

Augmentation of Creatine in the Heart

Zervou¹,

Whittington²,

Russell³

et al. 2015

MRMC

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Creatine is a principle component of the creatine kinase (CK) phosphagen system common to all vertebrates. It is found in excitable cells, such as cardiomyocytes, where it plays an important role in the buffering and transport of chemical energy to ensure that supply meets the dynamic demands of the heart. Multiple components of the CK system, including intracellular creatine levels, are reduced in heart failure, while ischaemia and hypoxia represent acute crises of energy provision. Elevation of myocardial creatine levels has therefore been suggested as potentially beneficial, however, achieving this goal is not trivial. This mini-review outlines the evidence in support of creatine elevation and critically examines the pharmacological approaches that are currently available. In particular, dietary creatine-supplementation does not sufficiently elevate creatine levels in the heart due to subsequent down-regulation of the plasma membrane creatine transporter (CrT). Attempts to increase passive diffusion and bypass the CrT, e.g. via creatine esters, have yet to be tested in the heart. However, studies in mice with genetic overexpression of the CrT demonstrate proof-of-principle that elevated creatine protects the heart from ischaemia-reperfusion injury. This suggests activation of the CrT as a major unmet pharmacological target. However, translation of this finding to the clinic will require a greater understanding of CrT regulation in health and disease and the development of small molecule activators.

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“…Once the liquid was cooled down to room temperature, the solution was acidified with glacial acetic acid and left for 3–5 h. The precipitate so obtained was filtered and washed with dilute acetic acid (5%). The obtained solid was triturated with hot DMF, filtered, and dried to yield the titled compound as a yellow solid. , …”

Section: Experimental Sectionmentioning

confidence: 99%

Further Studies on Triazinoindoles as Potential Novel Multitarget-Directed Anti-Alzheimer’s Agents

Patel

Kanhed

et al. 2020

ACS Chem. Neurosci.

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The inadequate clinical efficacy of the present anti-Alzheimer’s disease (AD) drugs and their low impact on the progression of Alzheimer’s disease in patients have revised the research focus from single targets to multitarget-directed ligands. A novel series of substituted triazinoindole derivatives were obtained by introducing various substituents on the indole ring for the development of multitarget-directed ligands as anti-AD agents. The experimental data indicated that some of these compounds exhibited significant anti-AD properties. Among them, 8-(piperidin-1-yl)-N-(6-(pyrrolidin-1-yl)hexyl)-5H-[1,2,4]triazino[5,6-b]indol-3-amine (60), the most potent cholinesterase inhibitor (AChE, IC50 value of 0.32 μM; BuChE, IC50 value of 0.21 μM), was also found to possess significant self-mediated Aβ1–42 aggregation inhibitory activity (54% at 25 μM concentration). Additionally, compound 60 showed strong antioxidant activity. In the PAMPA assay, compound 60 exhibited blood-brain barrier penetrating ability. An acute toxicity study in rats demonstrated no sign of toxicity at doses up to 2000 mg/kg. Furthermore, compound 60 significantly restored the cognitive deficits in the scopolamine-induced mice model and Aβ1–42-induced rat model. In the in silico ADMET prediction studies, the compound satisfied all the parameters of CNS acting drugs. These results highlighted the potential of compound 60 to be a promising multitarget-directed ligand for the development of potential anti-AD drugs.

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Ligand-based virtual screening identifies a family of selective cannabinoid receptor 2 agonists

Abstract: Graphical abstract

Cited by 20 publications

References 78 publications

Primary Macrophage Chemotaxis Induced by Cannabinoid Receptor 2 Agonists Occurs Independently of the CB2 Receptor

Primary Macrophage Chemotaxis Induced by Cannabinoid Receptor 2 Agonists Occurs Independently of the CB2 Receptor

Augmentation of Creatine in the Heart

Further Studies on Triazinoindoles as Potential Novel Multitarget-Directed Anti-Alzheimer’s Agents

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