作者：DAI; Wei; GAO; Xiang; LI; Yu-lei; YONG...respiratorydepressionglutamateampareceptormodulator
摘要：OBJECTIVE Respiratory depression hinders the use of anaesthetics and sedative hypnotics. For emergency use, specific antagonists are currently administered to counteract respiratory depression. However, antagonists are often short-lasting and can have multiple unexpected side effects. A novel AMPA receptor modulator LCX001, synthesized by our Institute of Medicinal Chemistry, is expected to relieve suppressed respiration. To explore the mechanism and impact of LCX001 on protection against respiratory depression. METHODS LCX001 was tested to alleviate respiratory depression triggered by opioid, propofol and pentobarbital in the plethysmography recording. The acetic acid writhing and hot-plate tests were conducted to evaluate potential analgesic effect of LCX001. Binding assay and whole-cell recording were used to analyze the property of LCX001 on positive modulation. The function of AMPA receptors were determined by location of receptors in the membrane and state of channel opening, and both processes were impressed by AMPA receptor regulatory proteins. According to the theory, the effect of LCX001 on the expression of stargazin was measured firstly by Western blotting. The variation of receptor surface location were observed by live cell imaging. The regulation on neuronal Ca2^+ and cell function was investigated intensively by Ca2^+ imaging to clarify mechanism of LCX001. RESULTS LCX001 effectively rescued and prevented opioid (fentanyl and TH-030418), propofol, and pentobarbital-induced respiratory depression by strengthening respiratory frequency and minute ventilation by 30% - 50% in rats. The acetic acid writhing test and hot-plate test revealed potent anti-nociceptive efficacy of LCX001 on increasing the inhibition rate and %MPE to 80% and 65% respectively, in contrast to some ampakines that did not affect analgesia. Furthermore, LCX001 potentiated [3H]AMPA and L-glutamate binding affinity to AMPA receptors, and facilitated glutamateevoked inward currents in HEK293 cells stably expressing GluA2(R). At 10 mm
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