Pharmacological characterization of a novel cannabinoid ligand, MDA19, for treatment of neuropathic pain

BACKGROUND: Cannabinoid receptor 2 (CB₂) agonists have recently gained attention as potential therapeutic targets in the management of neuropathic pain. In this study, we characterized the pharmacological profile of the novel compound N′-[(3Z)-1-(1-hexyl)-2-oxo-1,2-dihydro-3H-indol-3- ylidene]benzohydrazide (MDA19), a CB₂ agonist. METHODS: We used radioligand binding assays and multiple in vitro functional assays at human and rat CB₁ and CB₂ receptors. The effects of MDA19 in reversing neuropathic pain were assessed in various neuropathic pain models in rats and in CB₂^+/+ and CB₂^-/- mice. RESULTS: MDA19 displayed 4-fold-higher affinity at the human CB₂ than at the human CB₁ receptor (K_i = 43.3 ± 10.3 vs 162.4 ± 7.6 nM) and nearly 70-fold-higher affinity at the rat CB ₂ than at the rat CB₁ receptor (K_i = 16.3 ± 2.1 vs 1130 ± 574 nM). In guanosine triphosphate (GTP)γ[³⁵S] functional assays, MDA19 behaved as an agonist at the human CB₁ and CB₂ receptors and at the rat CB ₁ receptor but as an inverse agonist at the rat CB₂ receptor. In 3′,5′-cyclic adenosine monophosphate (cAMP) assays, MDA19 behaved as an agonist at the rat CB₁ receptor and exhibited no functional activity at the rat CB₂ receptor. In extracellular signal-regulated kinases 1 and 2 activation assays, MDA19 behaved as an agonist at the rat CB₂ receptor. MDA19 attenuated tactile allodynia produced by spinal nerve ligation or paclitaxel in a dose-related manner in rats and CB₂^+/+ mice but not in CB₂^-/- mice, indicating that CB₂ receptors mediated the effects of MDA19. MDA19 did not affect rat locomotor activity. CONCLUSIONS: We found that MDA19 exhibited a distinctive in vitro functional profile at rat CB₂ receptors and behaved as a CB₁/CB₂ agonist in vivo, characteristics of a protean agonist. MDA19 has potential for alleviating neuropathic pain without producing adverse effects in the central nervous system.