4-Oxo-1,4-dihydropyridines as Selective CB₂ Cannabinoid Receptor Ligands Part 2: Discovery of New Agonists Endowed with Protective Effect Against Experimental Colitis

Abstract

Further on to our earlier work on the 4-oxo-1,4-dihydropyridine, we describe herein our strategy to get access to potent selective CB₂ receptor agonists. Thus, we designed and synthesized 29 compounds, evaluated on both hCB₁ and hCB₂ cannabinoid receptors, and assessed 11 of them in the TNBS-induced colitis model in mice. Compound 48 was found to be the most efficient of our series, exhibiting an exquisite protection against experimental colitis, superior to the one observed after treatment with Pentasa.

Using Marijuana to cure Marijuana Addiction

“…CBD has been also claimed as a treatment to prevent diabetic neuropathy, a principal cause of blindness in the United States (US) [10][11][12]. CBD protects nerves, and it is derived from a plant which grows rather easily during summer time anywhere in the lower 48 states of the US (some areas need a greenhouse) [13][14][15]. Some strains of marijuana have higher compositions of THC and low compositions of CBD.…”

Conformational Restriction Leading to a Selective CB2 Cannabinoid Receptor Agonist Orally Active Against Colitis

“…Moreover, AM630 was shown to exacerbate colitis in wild-type mice. 5 Consistent with these data, we described a series of 4-oxo-1,4dihydropyridines (CB 2 selective agonists) in which the lead compound, ALICB573 (48 in ref 7), was shown to protect mice against experimental colitis when administered at 10 mg/kg (i.p. injection).…”

“…14 The affinities of target compounds 8−27 (Table 1) for the human cannabinoid receptors (hCB 1 and hCB 2 ) were determined by a competitive radioligand displacement assay using [ 3 H]-CP-55,940 as the radioligand for both the hCB 2 and hCB 1 receptors. 7 We also investigated the functional activity on the CB 2 receptor of four representative compounds of this series using a [ 35 S]-GTPγS binding assay ( Table 2). 16 The first step of this study was to evaluate the impact of the phenyl substituent at the C-4 position.…”

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.…”