Structural and pharmacological analysis of O-2050, a putative neutral cannabinoid CB1 receptor antagonist

Abstract

Rimonabant, the prototypic antagonist of cannabinoid CB 1 receptors, has been reported to have inverse agonist properties at higher concentrations, which may complicate its use as a tool for mechanistic evaluation of cannabinoid pharmacology. Consequently, recent synthesis efforts have concentrated on discovery of a neutral antagonist using a variety of structural templates. The purpose of this study was to evaluate the pharmacological properties of the putative neutral cannabinoid CB 1 receptor antagonist O-2050, a sulfonamide side chain analog of Δ 8 -tetrahydrocannabinol. O-2050 and related sulfonamide cannabinoids exhibited good affinity for both cannabinoid CB 1 and CB 2 receptors. While the other sulfonamide analogs produced cannabinoid agonist effects in vivo (e.g., activity suppression, antinociception, and hypothermia), O-2050 stimulated activity and was inactive in the other two tests. O-2050 also decreased food intake in mice, an effect that was reminiscent of that produced by rimonabant. Unlike rimonabant, however, O-2050 did not block the effects of cannabinoid agonists in vivo, even when administered i.c.v. In contrast, O-2050 antagonized the in vitro effects of cannabinoid agonists in [ 35 S]GTPγS and mouse vas deferens assays without having activity on its own in either assay. Further evaluation revealed that O-2050 fully and dose-dependently substituted for Δ 9 -tetrahydrocannabinol in a mouse drug discrimination procedure (a cannabinoid agonist effect) and that it inhibited forskolin-stimulated cyclic AMP signaling with a maximum efficacy of approximately half that of the full agonist CP55,940 [(−)-cis-3-[2-hydroxy-4(1,1-dimethylheptyl)phenyl]-trans-4-(3-hydroxy-propyl)cyclohexanol]. Together, these results suggest that O-2050 is not a viable candidate for classification as a neutral cannabinoid CB 1 receptor antagonist.

Biased Agonism of Three Different Cannabinoid Receptor Agonists in Mouse Brain Cortex

“…O-2050 was initially synthesized and described as a neutral CB 1 receptor antagonist, however, there are some evidences suggesting that is able to act as an inverse agonist or even as a partial agonist (Wiley et al, 2011). For this reason, and in order to validate O-2050 as a useful pharmacological tool to antagonize the effect mediated by cannabinoid receptors, [ 35 S]GTPγS SPAs were performed in mouse cortical membranes in the presence of O-2050 (10 μM) alone.…”

“…In this context, its good affinity for CB 2 receptors complicates its use as a tool to evaluate the unique contribution of CB 1 receptor (Wiley et al, 2011). We observed that, when alone, O-2050 activated the Gα z subunit.…”

“…O-2050 was chosen as a neutral cannabinoid antagonist. O-2050 has been proved to be a neutral CB 1 receptor antagonist in several studies (Canals and Milligan, 2008; Hudson et al, 2010; Brents et al, 2011; Wiley et al, 2011), with quite similar affinity for CB 1 and CB 2 receptors. Although, there is some data in the literature suggesting its activity as inverse or even partial agonist at CB 1 receptors in various tissues (Makwana et al, 2010; Wiley et al, 2011) in a previous work of our group, we showed that O-2050 has no effect over [ 35 S]GTPγS binding and behaves as an antagonist blocking WIN55212-2-mediated activation (Erdozain et al, 2012) ( Figure 1 ).…”

Synthesis and pharmacology of 1-alkyl-3-(1-naphthoyl)indoles: Steric and electronic effects of 4- and 8-halogenated naphthoyl substituents

“…35 Results of a [ 35 S]GTPγS binding assay showed that JWH-104 also functions as a low efficacy agonist at CB 1 receptors. Interestingly, JWH-104 did not substitute for THC in a drug discrimination procedure in mice (an animal model of marijuana-like intoxication), 36,37 suggesting that it does not produce the entire complement of cannabinoid effects seen with THC. JWH-415 has not been tested in the latter behavioral test.…”

The role of Endocannabinoid System in pathogenesis and therapy of obesity

“…Wiley i wsp. wykazali bowiem, że O-2050 może oddziaływać na receptory CB1 podobnie jak ich agoniści [61]. Biorąc pod uwagę zdolność tych substancji do zmniejszania łaknienia oraz brak skutków ubocznych po ich zastosowaniu w próbach przedklinicznych, mogą one okazać się bardziej efektywne w terapii otyłości niż odwrotni agoniści, tacy jak rimonabant.…”