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.2010 Jul;111(1):99-109.
doi: 10.1213/ANE.0b013e3181e0cdaf. Epub 2010 Jun 3.

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

Affiliations

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

Jijun J Xu et al. Anesth Analg.2010 Jul.

Abstract

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 CB(1) and CB(2) 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 CB(2) 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 CB2 than at the rat CB1 receptor (K(i) = 16.3 +/- 2.1 vs 1130 +/- 574 nM). In guanosine triphosphate (GTP)gamma[(35)S] functional assays, MDA19 behaved as an agonist at the human CB1 and CB2 receptors and at the rat CB1 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 CB(2) 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.

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Figures

Figure 1
Figure 1
Structure of MDA19 (N′-[(3Z)-1-(1-hexyl)-2-oxo-1,2-dihydro-3H-indol-3-ylidene]benzohydrazide). For details on synthesis and structure-activity relationships, see the article by Diaz et al.
Figure 2
Figure 2
Characterization of CP 55,940 (A) and MDA19 (B) in recombinant human CB1 and CB2 (hCB1 and hCB2) GTPγ[35S] assay systems. Levels of receptor activation were calculated and were expressed as percentages relative to the response to 1.0 µM CP 55,940. In this assay, MDA19 behaved as an agonist at the human CB2 receptor.
Figure 3
Figure 3
Characterization of CP 55,940 (A) and MDA19 (B) in recombinant rat CB1 and CB2 (rCB1 and rCB2) GTPγ[35S] assay systems. Levels of receptor activation were calculated and were expressed as percentages relative to the response to 1.0 µM CP 55,940. In this assay, MDA19 behaved as an inverse agonist at the CB2 receptor. The corresponding curve does not look like a typical sigmoidal curve because of 3 outliers. If we had excluded these outliers, the curve would have looked sigmoidal.
Figure 4
Figure 4
Characterization of CP 55,940 (A) and MDA19 (B) in cAMP activation assays at the rat CB1 and CB2 receptors. In this assay, MDA19 exhibited no activity at the rat CB2 receptor.
Figure 5
Figure 5
Characterization of MDA19 at the rat CB2 receptor in Erk (MAPK) activation assays. Stable Chinese hamster ovary cells expressing rat CB2 receptors were treated with MDA7 (a CB2 receptor–selective agonist); MDA19; or AM251 (a CB1 receptor–selective antagonist), AM630 (a CB2 receptor–selective antagonist), or pertussis toxin (PTX), followed by MDA19.
Figure 6
Figure 6
Effects of MDA19 administered by intraperitoneal (IP) injection on tactile allodynia in a spinal nerve ligation neuropathic pain model in rats. A, MDA19 increased the paw withdrawal threshold of the nerve-injured paw in a dose-dependent manner (n = 12 per group). B, MDA19 attenuated tactile allodynia in a dose-dependent manner (at 30 minutes, 50% effective dose = 9.1 mg/kg IP; 95% confidence interval = 6.9–11.8 mg/kg;n = 12 per group). C, Effects of CB2-selective antagonists on the antiallodynic effects of 10 mg/kg MDA19 in a spinal nerve ligation neuropathic pain model in rats (n = 6 per group). All drugs were administered by IP injection. Administration of 5 mg/kg AM630, a selective CB2 antagonist, had no effect. Administration of 5 mg/kg AM630 15 minutes before administration of MDA19 (AM630 + MDA19) reversed the antiallodynic effects of MDA19 (P < 0.05). Data are expressed as mean ± SEM. Vehicle = vehicle used for MDA19. Dimethyl sulfoxide (DMSO) was the solvent used for other compounds. %MPE = maximum peak effect; AUC = area under the curve.
Figure 7
Figure 7
Effects of WIN 55,212-2 administered by intraperitoneal (IP) injection on tactile allodynia in a spinal nerve ligation neuropathic pain model in rats. A, The time course of paw withdrawal threshold. B, WIN 55,212-2 attenuated tactile allodynia in a dose-dependent manner (at 15 minutes, 50% effective dose = 0.7mg/kg IP; 95% confidence interval = 0.5–0.9 mg/kg;n = 6 per group). Data are expressed as mean ± SEM. DMSO = dimethyl sulfoxide.
Figure 8
Figure 8
Effects of MDA19 administered by intraperitoneal injection on tactile allodynia in a paclitaxel-induced neuropathic pain model in rats (n = 5 per group). MDA19 produced antiallodynic effects that were significantly different (P < 0.05) (analysis of variance followed by the Tukey-Kramer test for multiple group comparison) from those of the vehicle, as evidenced by an increase in the %MPE (maximum peak effect) paw withdrawal threshold area under the curve (AUC).
Figure 9
Figure 9
Effect of MDA19 on locomotor activity. Exploratory behavior was tested in naïve animals in an open-field chamber after IP administration of the vehicle, MDA19, dimethyl sulfoxide (DMSO), WIN 55,212-2, or haloperidol (n = 6 per group). The following variables were scored for 60 minutes: distance traveled (A), ambulatory time (B), vertical activity (C), and number of zone entries (D). Statistical analyses were performed by analysis of variance followed by the Tukey-Kramer test for multiple group comparison. (Data presented for MDA19 and the vehicle were reproduced from Diaz et al. with permission from theJournal of Medicinal Chemistry.)
Figure 10
Figure 10
Effects of 10 mg/kg MDA19 administered by intraperitoneal injection on tactile allodynia in a paclitaxel-induced neuropathic pain model in CB2+/+ and CB2−/− mice (n = 5 per group). MDA19 suppressed mechanical allodynia in paclitaxel-treated CB2+/+ mice but did not show any effect in CB2−/− mice. *P < 0.05, ***P < 0.001 versus other groups, and **P < 0.01 versus CB2−/− mice groups (repeated-measures analysis of variance followed by the Tukey-Kramer test for multiple group comparison).
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