Structural Basis of Species-Dependent Differential Affinity of 6-Alkoxy-5-Aryl-3-Pyridinecarboxamide Cannabinoid-1 Receptor Antagonists

Abstract

6-Alkoxy-5-aryl-3-pyridincarboxamides, including the brain-, have been recently introduced as selective, high-affinity antagonists of the human cannabinoid-1 receptor (hCB 1 R). Binding analyses revealed two orders of magnitude lower affinity of these compounds for mouse and rat versus human CB 1 R, whereas the affinity of rimonabant is comparable for all three CB 1 Rs. Modeling of ligand binding to CB 1 R and binding assays with native and mutant (Ile105Met) hCB 1 Rs indicate that the Ile105 to Met mutation in rodent CB 1 Rs accounts for the species-dependent affinity of 14g and 14h. Our work identifies Ile105 as a new pharmacophore component for developing better hCB 1 R antagonists and invalidates rodent models for assessing the antiobesity efficacy of 14g and 14h.

Hybrid inhibitor of peripheral cannabinoid-1 receptors and inducible nitric oxide synthase mitigates liver fibrosis

“…The assay was performed as described previously (68). Briefly, binding affinity of the compounds to CB 1 R and CB 2 R was determined by radioligand displacement assays using 1 and 0.6 nM of [ 3 H]CP55,940 as the radioligand, respectively.…”

“…The assay was performed as described previously (68). Inverse agonism by MRI-1867 and rimonabant was determined in the absence of agonist, whereas their potency as antagonists (IC 50 ) was determined in the presence of the agonist CP55,940 (300 nM), which generated a CB 1 R-mediated increase in GTPγS binding at the ~EC 80 level.…”

“…The assay was performed as described previously (68). To determine inverse agonism, MRI-1867 or rimonabant was administered orally by gavage to male 8- to 10-week-old mice 1 hour prior to an oral bolus of 10% charcoal suspension in 5% gum arabic.…”

“…The assay was performed as described previously (68). Locomotor activity of drug-naive mice treated with an oral bolus dose of a CB 1 R antagonist or vehicle was quantified by the number of disruptions of infrared beams in 2 dimensions in an activity chamber.…”

Functional selectivity at G-protein coupled receptors: Advancing cannabinoid receptors as drug targets

“…Experimental nuances such as kinetics of response, response read-out bias, cell/tissue-specific variations, and the system-dependency of the observed pharmacological effects may influence the qualitative nature of biased signaling and its quantification [98]. Stereochemical [65] and species-dependent [99] pharmacological effects among orthosteric cannabinergic ligands and differences in their ability to elicit receptor oligomers that actively signal [100,101] may further extend the pharmacological scope of biased signaling at CBRs.…”