WAY‐318068: a novel, potent and selective noradrenaline re‐uptake inhibitor with activity in rodent models of pain and depression

Abstract

Background and purpose: Antidepressants, which raise the CNS concentrations of 5-HT and noradrenaline, are frequently used in the treatment of chronic pain; however, it is not known if increasing CNS noradrenaline levels alone is sufficient for efficacy, in part resulting from a lack of small molecules with sufficient selectivity. Experimental approach: In this report, we present the in vitro pharmacological and in vivo pharmacokinetic and pharmacological properties of the novel, orally available and CNS penetrant inhibitor of the noradrenaline transporter (NET), WAY-318068 (Key results: WAY-318068 is a potent and effective inhibitor of the NET with a Ki of 8.7 nM in a binding assay, and an IC50 of 6.8 nM in an assay of transporter function, without significant binding to the dopamine transporter. Furthermore, the compound has only weak activity at the 5-HT transporter, leading to a functional selectivity of greater than 2500-fold. It is orally bioavailable with substantial quantities of the compound found in the CNS after oral dosing. As measured by microdialysis in rats, the compound causes a robust and significant increase in cortical noradrenaline levels without affecting 5-HT. WAY-318068 was effective in models of acute, visceral, inflammatory, osteoarthritic, neuropathic, diabetic and bone cancer pain, as well as in traditional models of depression at doses that do not cause motor deficits. Conclusions and implications:Collectively, the present results support the conclusion that selectively increasing CNS levels of noradrenaline is sufficient for efficacy in models of depression and pain.

The Anti-Nociception Effect of Dezocine in a Rat Neuropathic Pain Model

“…[14,33] It is important to know that many drugs such as duloxetine, amitriptyline, and Thien-2-yl 1S, 2R-milnacipran analogues, are all mixed NET/SERT re-uptake inhibitors, which have been shown efficacy against NP in different animal models and in clinical use. [34][35][36][37] In our present study, the attenuation effect of allodynia and hyperalgesia in NP model by intraperitoneal injection of dezocine was found. Based on the role of NET and SERT in NP and our previous founding that NET and SERT are new targets of dezocine, we assume that the anti-nociception effect of dezocine may through the inhibition of norepinephrine and Fig.…”

The hippocampus and TNF: Common links between chronic pain and depression

“…Since these agents target multiple steps in the inflammatory and oxidative-nitrosative pathways, whether it is the combination of targeted effects or a single initiating effect that sets into motion antioxidant/anti-inflammatory cascade activation has yet to be determined. This is especially important in light of the finding that a selective increase in CNS levels of the monoamine norepinephrine was sufficiently efficacious in several models of pain and depression (Whiteside et al, 2010). However, these findings do support a role for hippocampal expressed TNF␣ in the rodent reserpine model of comorbid pain and depression.…”

α2 Adrenoceptor: a Target for Neuropathic Pain Treatment

“…3). The Pfizer (Wyeth) Group has extensively investigated the field of norepinephrine reuptake inhibitors, producing a large number of studies [128][129][130][131][132][133][134]. Maintaining the 3-amino-2-hydroxy-1-phenylpropyl fragment as suitable template for CNS drug, they selected a series of scaffolds such as aniline [128], indole [129] and benzimidazole [130].…”