Souza Ivana A, Gandini Maria A, Ali Md Yousof, Kricek Franz, Skouteris George, Zamponi Gerald W
Department of Clinical Neurosciences, Cumming School of Medicine, Hotchkiss Brain Institute, Alberta Children's Hospital Research Institute, University of Calgary, Calgary, AB, Canada.
Department of Experimental Neurosciences, Novassay SA, Biopôle, 1066, Epalinges, Switzerland.
Mol Brain. 2024 Aug 7;17(1):54. doi: 10.1186/s13041-024-01129-y.
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.
NVA1309是一种无法穿透大脑的下一代加巴喷丁类药物，已证实它能在一个由三个精氨酸组成的基序中的R243位点与Cavα2δ结合，该基序构成了加巴喷丁和普瑞巴林的结合位点。在本研究中，我们比较了NVA1309与米罗加巴林的作用效果，米罗加巴林是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、韩国和台湾地区被批准用于治疗带状疱疹后神经痛。NVA1309和米罗加巴林在体外均能抑制Cav2.2电流，并降低Cav2.2质膜表达，且效果优于普瑞巴林。经典结合残基精氨酸R243和新鉴定的结合残基赖氨酸K615的诱变可逆转米罗加巴林对Cav2.2电流的作用，但对NVA1309的作用无影响。
