Analgesic activity of imidazo[1,2-a]indole derivative and its involvement of TRPV1 and κ-opioid receptors

Introduction: Various analgesics, primarily nonsteroidal anti-inflammatory drugs (NSAIDs) and opioids, are used to relieve pain. On the account that opioids can cause respiratory depression, psychological and physical dependence, as well as addiction, and NSAIDs can cause gastro- and enteropathy, nephrotoxicity, bronchospasm, bleeding, and cardiovascular dysfunction, the search for new molecules exerting an analgesic effect through other cellular targets is relevant. The aim of this study was to evaluate the analgesic effect of a new imidazo[1,2-a]indole derivative in various pain models and its effect on TRPV1 and κ-opioid receptors. Materials and Methods. The median lethal dose (LD50) of the imidazo[1,2-a]indole derivative (lab code SV-1010) was determined in experiments on mice and rats. The analgesic effect of SV-1010 was studied by means of the hot plate test (in mice), tail-flick test (in rats), paw pressure test (in rats), abdominal constriction test (in mice), formalin test (in rats), and neuropathic pain test (in rats). In addition, the effect of SV-1010 on TRPV1 ion channels was examined (in a Chinese hamster ovary cell line with an induced expression of a rat TRPV1 channel), and the potential for κ-opioid receptor activation was tested (by means of molecular docking). SV-1010 and the reference drugs diclofenac, indomethacin, ketorolac, and pregabalin were administered intragastrically. Results and Discussion: SV-1010 is less toxic than diclofenac, indomethacin, and ketorolac, exhibits a pronounced analgesic effect, but exceeds diclofenac, indomethacin, ketorolac, and pregabalin by the potency and therapeutic index. The treatment sites for SV-1010 to exert its analgesic effect are the supraspinal, supraspinal + peripheral, spinal, and peripheral levels of pain sensitivity. Of note is the high selectivity of SV-1010 to blocking TRPV1 ion channel and activating κ-opioid receptors. Conclusion: Significantly lower acute toxicity (when compared to such of diclofenac, indomethacin, and ketorolac), high analgesic activity, and a wider therapeutic index (when compared to such of diclofenac, indomethacin, ketorolac, and pregabalin) make SV-1010 promising for further preclinical study.