In vitro and in vivo characterization of A‐796260: a selective cannabinoid CB₂ receptor agonist exhibiting analgesic activity in rodent pain models

Abstract

Background and purpose: Selective cannabinoid CB 2 receptor agonists have demonstrated analgesic activity across multiple preclinical pain models. AM1241 is an indole derivative that exhibits high affinity and selectivity for the CB 2 binding site and broad spectrum analgesic activity in rodent models, but is not an antagonist of CB 2 in vitro functional assays. Additionally, its analgesic effects are m-opioid receptor-dependent. Herein, we describe the in vitro and in vivo pharmacological properties of A-796260, a novel CB 2 agonist. Experimental approach: A-796260 was characterized in radioligand binding and in vitro functional assays at rat and human CB 1 and CB 2 receptors. The behavioural profile of A-796260 was assessed in models of inflammatory, post-operative, neuropathic, and osteoarthritic (OA) pain, as well as its effects on motor activity. The receptor specificity was confirmed using selective CB 1 , CB 2 and m-opioid receptor antagonists. Key results: A-796260 exhibited high affinity and agonist efficacy at human and rat CB 2 receptors, and was selective for the CB 2 vs CB 1 subtype. Efficacy in models of inflammatory, post-operative, neuropathic and OA pain was demonstrated, and these activities were selectively blocked by CB 2 , but not CB 1 or m-opioid receptor-selective antagonists. Efficacy was achieved at doses that had no significant effects on motor activity. Conclusions and implications: These results further confirm the therapeutic potential of CB 2 receptor-selective agonists for the treatment of pain. In addition, they demonstrate that A-796260 may be a useful new pharmacological compound for further studying CB 2 receptor pharmacology and for evaluating its role in the modulation of pain.

Characterization of a Cannabinoid CB2Receptor-Selective Agonist, A-836339 [2,2,3,3-Tetramethyl-cyclopropanecarboxylic Acid [3-(2-Methoxy-ethyl)-4,5-dimethyl-3H-thiazol-(2Z)-ylidene]-amide], Using in Vitro Pharmacological Assays, in Vivo Pain Models, and Pharmacological Magnetic Resonance Imaging

“…Furthermore, the A-836339-evoked effects were blocked by a CB 2 , but not a CB 1 , receptor-selective antagonist, indicating that the antihyperalgesic effects of A-836339 are mediated through the CB 2 , but not the CB 1 , receptor. In addition, unlike AM1241 (Ibrahim et al, 2005;Yao et al, 2008), the effects evoked by A-836339 do not involve the -opioid receptor, a finding similar to those previously reported for A-796260 and L-768,242 (Whiteside et al, 2005). Although none of these ligands exhibits appreciable binding affinity to the -opioid receptor (IC 50 Ͼ 10 M), AM1241-mediated effect is fully blocked by naloxone.…”

A PET Brain Reporter Gene System Based on Type 2 Cannabinoid Receptors

“…In our assay, GW405833 shows a 10-fold lower affinity for hCB 2 and behaved as an inverse agonist in our GTPgS assay. Our results are in accordance with those of Yao et al, who reported that GW405833 is a potent inverse agonist in both hCB 2 (16,29,30).…”

Synthesis, biological activity and molecular modeling of new biphenylic carboxamides as potent and selective CB2 receptor ligands

“…Noteworthy, in preclinical studies, analgesic and antiinflammatory properties have been described for both CB2 receptor agonists [21,22] and CB2 receptor inverse agonists [23,24]. A similar trend can be evidenced regarding bone remodelling and osteoporosis [25e28].…”