PDF(Pubmed)
Abstract：
NVA1309 is a non-brain penetrant next-generation gabapentinoid shown to bind Cavα2δ at R243 within a triple Arginine motif forming the binding site for gabapentin and pregabalin. In this study we have compared the effects of NVA1309 with Mirogabalin, a gabapentinoid drug with higher affinity for the voltage-gated calcium channel subunit Cavα2δ-1 than pregabalin which is approved for post-herpetic neuralgia in Japan, Korea and Taiwan. Both NVA1309 and mirogabalin inhibit Cav2.2 currents in vitro and decrease Cav2.2 plasma membrane expression with higher efficacy than pregabalin. Mutagenesis of the classical binding residue arginine R243 and the newly identified binding residue lysine K615 reverse the effect of mirogabalin on Cav2.2 current, but not that of NVA1309.
摘要：
NVA1309是一种非脑渗透剂的下一代加巴喷丁，可在三重精氨酸基序内与R243处的Cavα2δ结合，形成加巴喷丁和普瑞巴林的结合位点。在这项研究中，我们比较了NVA1309与米罗加巴林的效果，一种加巴喷丁类药物，对电压门控钙通道亚基Cavα2δ-1的亲和力高于普瑞巴林，在日本被批准用于疱疹后神经痛，韩国和台湾。NVA1309和米罗加巴林均在体外抑制Cav2.2电流并降低Cav2.2质膜表达,其效力高于普瑞巴林。经典结合残基精氨酸R243和新鉴定的结合残基赖氨酸K615的诱变逆转了米加巴林对Cav2.2电流的影响，但不是NVA1309。
