3-(1′,1′-Dimethylbutyl)-1-deoxy-Δ8-THC and related compounds: synthesis of selective ligands for the CB2 receptor

Huffman, John W.; Liddle, John; Yu, Shu; Aung, Mie Mie; Abood, Mary E.; Wiley, Jenny L.; Martin, Billy R.

doi:10.1016/s0968-0896(99)00219-9

Cited by 264 publications

(202 citation statements)

References 15 publications

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“…In this study, we used the selective CB 2 receptor agonist JWH133 developed by Huffman et al (16), which exhibits ϳ200-fold selectivity over CB 1 receptors. Its potency has been underlined in numerous in vivo studies (2,3,24,38).…”

Section: Discussionmentioning

confidence: 99%

Cannabinoid receptor CB₂ protects against balloon-induced neointima formation

Molica

Matter

Burger

et al. 2012

American Journal of Physiology-Heart and Circulatory Physiology

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Cannabinoid receptor CB2 activation inhibits inflammatory proliferation and migration of vascular smooth muscle cells in vitro. The potential in vivo relevance of these findings is unclear. We performed carotid balloon distension injury in hypercholesterolemic apolipoprotein E knockout (ApoE−/−) mice receiving daily intraperitoneal injection of the CB2 agonist JWH133 (5 mg/kg) or vehicle, with the first injection given 30 min before injury. Alternatively, we subjected CB2−/− and wild-type (WT) mice to balloon injury. We determined CB2 mRNA and protein expression in dilated arteries of ApoE−/− mice. Neointima formation was assessed histologically. We used bone marrow-derived murine CB2−/− and WT macrophages to study adhesion to plastic, fibronectin, or collagen, and migration was assayed by modified Boyden chamber. Aortic smooth muscle cells were isolated to determine in vitro proliferation rates. We found increased vascular CB2 expression in ApoE−/− mice in response to balloon injury. Seven to twenty-one days after dilatation, injured vessels of JWH133-treated mice had less intimal nuclei numbers as well as intimal and medial areas, associated with less staining for proliferating cells, smooth muscle cells, and macrophages. Complete endothelial repair was observed after 14 days in both JWH133- and vehicle-treated mice. CB2 deficiency resulted in increased intima formation compared with WT, whereas JWH133 did not affect intimal formation in CB2−/− mice. Apoptosis rates assessed by in situ terminal deoxynucleotidyl transferase dUTP-mediated nick-end labeling staining 1 h postballooning were significantly higher in the CB2 knockouts. In vitro, bone marrow-derived CB2−/− macrophages showed enhanced adherence and migration compared with WT cells and elevated mRNA levels of adhesion molecules, chemokine receptors CCR1 and 5, and chemokine CCL2. Proliferation rates were significantly increased in CB2−/− smooth muscle cells compared with WT. In conclusion, pharmacological activation or genetic deletion of CB2 receptors modulate neointima formation via protective effects in macrophages and smooth muscle cells.

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Section: Discussionmentioning

confidence: 99%

Cannabinoid receptor CB₂ protects against balloon-induced neointima formation

Molica

Matter

Burger

et al. 2012

American Journal of Physiology-Heart and Circulatory Physiology

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“…JWH-133 has a very high affinity for the CB2R (Kiϭ3.4 nmol/L), but low affinity for the CB1R (Kiϭ677 nmol/L). 21 …”

Section: Methodsmentioning

confidence: 99%

Cannabinoid Type 2 Receptor Activation Downregulates Stroke-Induced Classic and Alternative Brain Macrophage/Microglial Activation Concomitant to Neuroprotection

Zarruk

Fernández-López

García-Yébenes

et al. 2012

Stroke

178

147

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Background and Purpose— Ischemic stroke continues to be one of the main causes of death worldwide. Inflammation accounts for a large part of damage in this pathology. The cannabinoid type 2 receptor (CB2R) has been proposed to have neuroprotective properties in neurological diseases. Therefore, our aim was to determine the effects of the activation of CB2R on infarct outcome and on ischemia-induced brain expression of classic and alternative markers of macrophage/microglial activation. Methods— Swiss wild-type and CB2R knockout male mice were subjected to a permanent middle cerebral artery occlusion. Mice were treated with either a CB2R agonist (JWH-133), with or without a CB2R antagonist (SR144528) or vehicle. Infarct outcome was determined by measuring infarct volume and neurological outcome. An additional group of animals was used to assess mRNA and protein expression of CB2R, interleukin (IL)-1β, IL-6, tumor necrosis factor α (TNF-α), monocyte chemoattractant protein–1 (MCP-1), macrophage inflammatory peptide (MIP) –1α, RANTES, inducible nitric oxide synthase (iNOS), cyclooxygenase-2, IL-4, IL-10, transforming growth factor β (TGF-β), arginase I, and Ym1. Results— Administration of JWH-133 significantly improved infarct outcome, as shown by a reduction in brain infarction and neurological impairment. This effect was reversed by the CB2R antagonist and was absent in CB2R knockout mice. Concomitantly, administration of JWH-133 led to a lower intensity of Iba1+ microglia/macrophages and a decrease in middle cerebral artery occlusion–induced gene expression of both classic (IL-6, TNF-α, MCP-1, MIP-1α, RANTES, and iNOS) and alternative mediators/markers (IL-10, TGF-β, and Ym1) of microglial/macrophage activation after permanent middle cerebral artery occlusion. Conclusions— The inhibitory effect of CB2R on the activation of different subpopulations of microglia/macrophages may account for the protective effect of the selective CB2R agonist JWH-133 after stroke.

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“…JWH-133 was prepared in J.W. Huffman's laboratory (25). WIN-55,212-2 was from Sigma-Aldrich (St. Louis, Missouri, USA).…”

Section: Methodsmentioning

confidence: 99%

Inhibition of skin tumor growth and angiogenesis in vivo by activation of cannabinoid receptors

Casanova¹,

Blázquez²,

et al. 2003

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Nonmelanoma skin cancer is one of the most common malignancies in humans. Different therapeutic strategies for the treatment of these tumors are currently being investigated. Given the growth-inhibiting effects of cannabinoids on gliomas and the wide tissue distribution of the two subtypes of cannabinoid receptors (CB1 and CB2), we studied the potential utility of these compounds in anti–skin tumor therapy. Here we show that the CB1 and the CB2 receptor are expressed in normal skin and skin tumors of mice and humans. In cell culture experiments pharmacological activation of cannabinoid receptors induced the apoptotic death of tumorigenic epidermal cells, whereas the viability of nontransformed epidermal cells remained unaffected. Local administration of the mixed CB1/CB2 agonist WIN-55,212-2 or the selective CB2 agonist JWH-133 induced a considerable growth inhibition of malignant tumors generated by inoculation of epidermal tumor cells into nude mice. Cannabinoid-treated tumors showed an increased number of apoptotic cells. This was accompanied by impairment of tumor vascularization, as determined by altered blood vessel morphology and decreased expression of proangiogenic factors (VEGF, placental growth factor, and angiopoietin 2). Abrogation of EGF-R function was also observed in cannabinoid-treated tumors. These results support a new therapeutic approach for the treatment of skin tumors

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3-(1′,1′-Dimethylbutyl)-1-deoxy-Δ8-THC and related compounds: synthesis of selective ligands for the CB2 receptor

Cited by 264 publications

References 15 publications

Cannabinoid receptor CB₂ protects against balloon-induced neointima formation

Cannabinoid receptor CB₂ protects against balloon-induced neointima formation

Cannabinoid Type 2 Receptor Activation Downregulates Stroke-Induced Classic and Alternative Brain Macrophage/Microglial Activation Concomitant to Neuroprotection

Inhibition of skin tumor growth and angiogenesis in vivo by activation of cannabinoid receptors

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3-(1′,1′-Dimethylbutyl)-1-deoxy-Δ8-THC and related compounds: synthesis of selective ligands for the CB2 receptor

Cited by 264 publications

References 15 publications

Cannabinoid receptor CB2 protects against balloon-induced neointima formation

Cannabinoid receptor CB2 protects against balloon-induced neointima formation

Cannabinoid Type 2 Receptor Activation Downregulates Stroke-Induced Classic and Alternative Brain Macrophage/Microglial Activation Concomitant to Neuroprotection

Inhibition of skin tumor growth and angiogenesis in vivo by activation of cannabinoid receptors

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Cannabinoid receptor CB₂ protects against balloon-induced neointima formation

Cannabinoid receptor CB₂ protects against balloon-induced neointima formation