3-Carboxamido-5-aryl-isoxazoles as new CB2 agonists for the treatment of colitis

Intestinal Autophagy and Its Pharmacological Control in Inflammatory Bowel Disease

“…In addition, activating CB2R was also demonstrated to alleviate colitis through inhibiting T cell activation and promote apoptosis in IL-10-deficient mice (162). In the recent years, several kinds of CB2R activators have been successfully applied in the treatment of colitis animal model (117, 163, 164). For example, activating CB2R by HU-308, a selective CB2R agonist, contributed to the enhancement of macrophage autophagy through the AMPK-mTOR-P70S6K signaling pathway, and further inhibited the NLRP3 inflammasome activation, thus reducing the level of IL-1β and alleviating the progression of DSS-induced colitis in mice (117) (illustrated in Figure 2).…”

Endocannabinoids

“…This was first shown using nonselective CB 1 and CB 2 agonists (e.g., WIN55212, HU-210) but also using CB 1 -selective agonists such as ACEA or CB 2selective agonists such as JWH-133 (Alhouayek and Muccioli 2012). The efficacy of JWH-133 was shown in numerous IBD models (Singh et al 2012;Storr et al 2009;Kimball et al 2006), further supporting the strategy of selectively activating the CB 2 receptor in the context of colon inflammation and prompting the development of novel CB 2 agonists with anti-inflammatory properties (Tourteau et al 2013;El Bakali et al 2012). The CNS side effects associated with CB 1 receptor activation are somewhat hampering the study of centrally active CB 1 agonists in the context of colon inflammation.…”

The gastrointestinal tract – a central organ of cannabinoid signaling in health and disease

“…Activation of the CB 1 or CB 2 receptor with specific agonists also protected from colitis. Accordingly, genetic ablation or pharmacological antagonism of CB 1 or CB 2 receptors left mice more susceptible to intestinal inflammation.…”