Grigoriadis Dimitri E, Smith Evan, Hoare Sam R J, Madan Ajay, Bozigian Haig
Neurocrine Biosciences Inc., San Diego, California (D.E.G., E.S., H.B.); Pharmechanics, Wayne, Pennsylvania (S.R.J.H.); and Crinetics Pharmaceuticals, San Diego, California (A.M.)
Neurocrine Biosciences Inc., San Diego, California (D.E.G., E.S., H.B.); Pharmechanics, Wayne, Pennsylvania (S.R.J.H.); and Crinetics Pharmaceuticals, San Diego, California (A.M.).
J Pharmacol Exp Ther. 2017 Jun;361(3):454-461. doi: 10.1124/jpet.116.239160. Epub 2017 Apr 12.
The vesicular monoamine transporter 2 (VMAT2) is an integral presynaptic protein that regulates the packaging and subsequent release of dopamine and other monoamines from neuronal vesicles into the synapse. Valbenazine (NBI-98854), a novel compound that selectively inhibits VMAT2, is approved for the treatment of tardive dyskinesia. Valbenazine is converted to two significant circulating metabolites in vivo, namely, (+)--dihydrotetrabenazine (R,R,R-HTBZ) and a mono-oxy metabolite, NBI-136110. Radioligand-binding studies were conducted to assess and compare valbenazine, tetrabenazine, and their respective metabolites in their abilities to selectively and potently inhibit [H]-HTBZ binding to VMAT2 in rat striatal, rat forebrain, and human platelet homogenates. A broad panel screen was conducted to evaluate possible off-target interactions of valbenazine, R,R,R-HTBZ, and NBI-136110 at >80 receptor, transporter, and ion channel sites. Radioligand binding showed R,R,R-HTBZ to be a potent VMAT2 inhibitor in homogenates of rat striatum (K = 1.0-2.8 nM), rat forebrain (K = 4.2 nM), and human platelets (K = 2.6-3.3 nM). Valbenazine (K = 110-190 nM) and NBI-136110 (K = 160-220 nM) also exhibited inhibitory effects on VMAT2, but with lower potency than R,R,R-HTBZ. Neither valbenazine, R,R,R-HTBZ, nor NBI-136110 had significant off-target interactions at serotonin (5-HT, 5-HT, 5-HT) or dopamine (D or D) receptor sites. In vivo studies measuring ptosis and prolactin secretion in the rat confirmed the specific and dose-dependent interactions of tetrabenazine and R,R,R-HTBZ with VMAT2. Evaluations of potency and selectivity of tetrabenazine and its pharmacologically active metabolites were also performed. Overall, the pharmacologic characteristics of valbenazine appear consistent with the favorable efficacy and tolerability findings of recent clinical studies [KINECT 2 (NCT01733121), KINECT 3 (NCT02274558)].
囊泡单胺转运体2（VMAT2）是一种完整的突触前蛋白，它调节多巴胺和其他单胺从神经元囊泡的包装以及随后向突触的释放。缬苯那嗪（NBI-98854）是一种选择性抑制VMAT2的新型化合物，已被批准用于治疗迟发性运动障碍。缬苯那嗪在体内转化为两种主要的循环代谢物，即（+）-二氢丁苯那嗪（R,R,R-HTBZ）和一种单氧代谢物NBI-136110。进行放射性配体结合研究以评估和比较缬苯那嗪、丁苯那嗪及其各自的代谢物在大鼠纹状体、大鼠前脑和人血小板匀浆中选择性和有效抑制[H]-HTBZ与VMAT2结合的能力。进行了广泛的筛选以评估缬苯那嗪、R,R,R-HTBZ和NBI-136110在>80个受体、转运体和离子通道位点的可能脱靶相互作用。放射性配体结合显示R,R,R-HTBZ在大鼠纹状体匀浆（K = 1.0 - 2.8 nM）、大鼠前脑（K = 4.2 nM）和人血小板（K = 2.6 - 3.3 nM）中是一种有效的VMAT2抑制剂。缬苯那嗪（K = 110 - 190 nM）和NBI-136110（K = 160 - 220 nM）也对VMAT2表现出抑制作用，但效力低于R,R,R-HTBZ。缬苯那嗪、R,R,R-HTBZ和NBI-136110在5-羟色胺（5-HT、5-HT、5-HT）或多巴胺（D或D）受体位点均无明显的脱靶相互作用。在大鼠中测量上睑下垂和催乳素分泌的体内研究证实了丁苯那嗪和R,R,R-HTBZ与VMAT2的特异性和剂量依赖性相互作用。还对丁苯那嗪及其药理活性代谢物的效力和选择性进行了评估。总体而言，缬苯那嗪的药理特性似乎与近期临床研究[KINECT 2（NCT01733121），KINECT 3（NCT02274558）]的良好疗效和耐受性结果一致。
