Abstract
The α-aminoamide family of sodium ion channel blockers have exhibited analgesic effects on neuropathic pain. Here, a series of novel α-aminoamides containing an indole ring were designed and synthesized. These compounds were evaluated in mice using a formalin test and they exhibited significant anti-allodynia activities. However, the analgesic mechanism of these compounds remains unclear; a subset of the synthesized compounds can only moderately inhibit the sodium ion channel, Nav1.7, in a whole-cell patch clamp assay. Overall, these results suggest that introduction of an indole moiety to α-aminoamide derivatives can significantly improve their bioactivity and further study is warranted.
Highlights
Neuropathic pain is a chronic disease caused by lesion or dysfunction of the somatosensory system [1,2]
Recent studies have suggested that voltage-gated sodium channels (VGSCs) may be an ideal therapeutic target for neuropathic pain
Such slight chemical structural differences between ralfinamide and safinamide result in dramatic changes in pharmacological activity, indicating that delicate structure-activity relationship (SAR) inspection is needed for these types of compounds
Summary
Neuropathic pain is a chronic disease caused by lesion or dysfunction of the somatosensory system [1,2]. Some α-aminoamide derivatives, including ralfinamide (Figure 1), are potential anti-neuropathic drug candidates. Data from animal models of inflammatory and neuropathic pain have suggested that ralfinamide exhibits a significant analgesic effect while having a well-tolerated safety profile [6,7,8]. Ralfinamide is the only small molecule drug in a late-stage clinical trial for the treatment of neuropathic pain [9,10,11,12,13]. The only structural difference between ralfinamide and safinamide is the position of the fluoro substituent (Figure 1). Such slight chemical structural differences between ralfinamide and safinamide result in dramatic changes in pharmacological activity, indicating that delicate structure-activity relationship (SAR) inspection is needed for these types of compounds.
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