JTE 907

The cannabinoid CB2 receptor inverse agonist JTE-907 suppresses spontaneous itch-associated responses of NC mice, a model of atopic dermatitis.[Pubmed:16824511]

Eur J Pharmacol. 2006 Aug 7;542(1-3):179-83.

JTE-907, N-(benzo[1,3]dioxol-5-ylmethyl)-7-methoxy-2-oxo-8-pentyloxy-1,2-dihydroquinoline- 3-carboxamide, is a selective cannabinoid CB2 receptor antagonist/inverse agonist. The anti-pruritic activity of JTE-907 was studied in NC mice with chronic dermatitis, a model of atopic dermatitis. The oral dose of JTE-907 (1 and 10 mg/kg/day), an immunosuppressant agent tacrolimus (1 mg/kg/day) and a glucocorticoid betamethasone 17-valerate (1 mg/kg/day) for 20 days suppressed the spontaneous scratching and cutaneous nerve activity of NC mice. JTE-907 (10, but not 1, mg/kg) and tacrolimus, but not betamethasone, tended to alleviate the dermatitis. Betamethasone inhibited the body weight gain. These results suggest that JTE-907 suppresses spontaneous itch-associated responses of NC mice without adverse effects such as weight loss.

Upregulation of the expression of inflammatory and angiogenic markers in human adipocytes by a synthetic cannabinoid, JTE-907.[Pubmed:20603779]

Horm Metab Res. 2010 Sep;42(10):710-7.

Inflammation in adipose tissue is a characteristic of obesity and the metabolic syndrome. It is suggested that the endocannabinoid system is involved in the regulation of inflammatory and angiogenic processes within the tissue. Human subcutaneous preadipocytes (Zen Bio) were used as the source of human preadipocytes or adipocytes. Gene expression was examined by RT-PCR and real-time PCR. The secretion of inflammation-related proteins was determined by an ELISA array. In experiments on adipocytes treated at day 14 post-differentiation, JTE-907, a synthetic cannabinoid, upregulated the expression of key inflammatory markers - IL-6, MCP-1 and IL-1 beta - and angiogenic factors - VEGF and ANGPTL4 - at 10 microM after 20 h of treatment, having also increased the expression of TRPV1 at 10 microM. JTE-907 showed no effect after 4 h. The ELISA array showed a 2.6-fold increase in IL-6 protein release. The effect of JTE-907 was inhibited by AM251 (CB1 antagonist), and partially by arachidonyl serotonin (TRPV1 and FAAH antagonist). The CB2 antagonist, AM630, partially upregulated the effect of JTE-907. Preadipocytes fed 14 days after 100% confluence exhibited downregulation of CB1, MCP-1, and IL-1 beta, 20 h after having been exposed to JTE-907. CB1 and TRPV1 receptors participate in the regulation of several inflammatory and angiogenic factors in human adipocytes, indicating their potential value as targets for the treatment of disorders related to obesity.

In vitro and in vivo pharmacological characterization of JTE-907, a novel selective ligand for cannabinoid CB2 receptor.[Pubmed:11160626]

J Pharmacol Exp Ther. 2001 Feb;296(2):420-5.

JTE-907 [N-(benzo[1,3]dioxol-5-ylmethyl)-7-methoxy-2-oxo-8-pentyloxy-1,2-dihydroquinoline -3-carboxamide] was evaluated in vitro and in vivo as a novel selective ligand for cannabinoid receptor of peripheral type (CB2). The compound binds with high affinity to human CB2 or mouse CB2 expressed on CHO cell membrane and to rat CB2 on splenocytes. The K(i) affinities for human, mouse, and rat CB2 were 35.9, 1.55, and 0.38 nM, respectively. The selectivity ratio for the CB2 receptors compared with central nervous type receptors (CB1) of human (expressed on CHO cells), and mouse and rat CB1 on cerebellum were 66, 684, and 2760, respectively. JTE-907 showed concentration-dependent increase of forskolin-stimulated cAMP production in CHO cells expressing human and mouse CB2 in vitro, i.e., JTE-907 behaved as an inverse agonist, which is in contrast to Win55212-2 that reduces cAMP as an agonist. JTE-907 dosed orally inhibited carrageenin-induced mouse paw edema dose dependently. The same in vivo effect was observed with other cannabinoid receptor ligands such as SR144528, Delta(9)-tetrahydrocannabinol (THC), and Win55212-2. This is the first report that a CB2-selective inverse agonist, JTE-907, has an anti-inflammatory effect in vivo, and how the inverse agonist showed the same effect as Win55212-2 and Delta(9)-THC is discussed.

Involvement of cannabinoid CB(2) receptor-mediated response and efficacy of cannabinoid CB(2) receptor inverse agonist, JTE-907, in cutaneous inflammation in mice.[Pubmed:16153638]

Eur J Pharmacol. 2005 Sep 27;520(1-3):164-71.

Involvement of cannabinoid CB(2) receptor and effect of cannabinoid CB(2) receptor antagonist/inverse agonists on cutaneous inflammation were investigated. Mice ears topically exposed to an ether-linked analogue of 2-arachidonoylglycerol (2-AG-E) or selective cannabinoid CB(2) receptor agonist, {4-[4-(1,1-dimethylheptyl)-2,6-dimethoxy-phenyl]-6.6-dimethyl-bicyclo[3.1.1]hept- 2-en-2-yl}-methanol (HU-308), had early and late ear swelling (0--24 h and 1--8 days after exposure, respectively). Both types of responses induced by 2-AG-E were significantly suppressed by oral administration of cannabinoid CB(2) receptor antagonist/inverse agonists, [N-(benzo[1,3]dioxol-5-ylmethyl)-7-methoxy-2-oxo-8-pentyloxy-1,2-dihydroquinoline -3-carboxamide] (JTE-907) and {N-[(1S)-endo-1,3,3-trimethylbicyclo[2.2.1]heptan-2 yl]5-(4-chloro-3-methyl-phenyl)-1-(4-methylbenzyl)pyrazole-3-carboxamide}} (SR 144528). In contrast, JTE-907 did not affect arachidonic acid-induced swelling. Orally administered JTE-907 (0.1-10 mg/kg) and SR 144528 (1 mg/kg) also produced significant inhibition of dinitrofluorobenzene-induced ear swelling, with increased cannabinoid CB(2) receptor mRNA expression observed in the inflamed ear. These results suggest that cannabinoid CB(2) receptor is partially involved in local inflammatory responses and cannabinoid CB(2) receptor antagonist/inverse agonist has beneficial effects on ear swelling.