Analgesic Activity of the Kappa Opioid Receptor Agonist RU-1205 in Rats

Abstract

Introduction: Opioid analgesics are the most efficient and widely used drugs for the management of moderate to severe pain. However, side effects associated with mu receptor activation, such as respiratory depression, tolerance and physical dependence severely limit their clinical application. Currently, the kappa-opioid system is the most attractive in terms of the clinical problem of pain, because kappa-agonists do not cause euphoria and physical dependence. The purpose of this study was to evaluate the antinociceptive effect of the novel compound - RU-1205. Methods: The analgesic activity of RU-1205 was studied on nociceptive models that characterize the central and peripheral pathways of pain sensitivity (hot plate test, electrically induced vocalisation, formalin test, writhing test). Results: RU-1205 exhibited highly potent antinociceptive effects in rodent models of acute pain with ED50 values of 0.002 - 0.49 mg /kg. Pretreatment with the κ-opioid receptor antagonist norBinaltorphimine significantly attenuated the analgesic activity of investigated substance in a hot plate test. Conclusions: It was established that the compound shows a significant dose-dependent central and peripheral analgesic effect. It was assumed kappa-opioidergic mechanism of analgesic effect of RU-1205.

Pharmacokinetic Properties of a New Kappa-Opioid Analgesic Ru-1205 Compound at a Single Peroral Administration

“…В ранее проведенных исследованиях было выявлено, что соединение оказывает дозозависимый анальгетический эффект, а среднеэффективная доза RU-1205 при пероральном пути введения составляет 5 мг/кг [8]. Основной параметр, характеризующий степень биологической доступности препарата, площадь под фармакокинетической кривой RU-1205, увеличивается с увеличением дозы линейно [40].…”

“…Изучение обезболивающих свойств RU-1205 на экспериментальных ноцицептивных моделях показало, что исследуемое соединение по анальгетической активности превосходит морфин и буторфанол [7] и, в отличие от препаратов сравнения, не вызывает угнетения дыхания и не обладает фармакологическими свойствами, которые можно расценить как специфические предикторы способности вещества формировать физическую зависимость, вызывать аверсию или аддикцию [8,9]. Согласно современной концепции терапии выраженной хронической боли, неинвазивные лекарственные формы опиоидных анальгетиков признаны наиболее эффективными и безопасными препаратами, обеспечивающими наилучшее качество жизни пациентов (кроме заключительных стадий заболевания).…”

Distribution, excretion and metabolic pathways of a single parenteral administration of kappa-opioid receptor agonist RU-1205

“…In vitro, this drug was found to have a significant analgesic activity due to its agonistic effect on kappa opioid receptors (Grechko et al 2017). In vivo, RU-1205 demonstrated a significant pain relieving effect exceeding that of butorphanol and morphine (Spasov et al 2018), without any respiratory depression, development of analgesic tolerance and physical dependency (Grechko et al 2017;Litvinov et al 2017).…”

Synthesis and Pharmacological Evaluation of Novel 2,3,4,5-tetrahydro[1,3]diazepino[1,2-a]benzimidazole Derivatives as Promising Anxiolytic and Analgesic Agents

“…Derivatives of 2-aminomethylbenzimidazole showed high analgesic and anti-inflammatory activity in the models “Acetic acid-induced writhing” and “Carrageenan-induced paw edema” in mice, comparable to nimesulide at a dose of 50 mg/kg [ 17 , 18 , 19 ]. Compound RU-1205is a new highly selective central kappa-opioid agonist, for which an analgesic activity has been previously shown [ 20 ], with antiepileptoform and anticonvulsant components, confirmed in isolated experiments with maximal electroshock neurons [ 21 ]. The anxiolytic potential of benzodiazepine derivatives has been confirmed by many years of clinical practice, and according to the data of modern research, the neuropsychotropic properties of these compounds are used in many areas of medical science.…”