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 being developed for the treatment of tardive dyskinesia. Valbenazine is converted to two significant circulating metabolites in vivo, namely, (+)-α-dihydrotetrabenazine (R,R,R-DHTBZ) 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 [3H]-DHTBZ 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-DHTBZ, and NBI-136110 at >80 receptor, transporter, and ion channel sites. Radioligand binding showed R,R,R-DHTBZ to be a potent VMAT2 inhibitor in homogenates of rat striatum (Ki=1.0-2.8 nM), rat forebrain (Ki=4.2 nM), and human platelets (Ki=2.6-3.3 nM). Valbenazine (Ki=110-190 nM) and NBI 136110 (Ki=160-220 nM) also exhibited inhibitory effects on VMAT2, but with lower potency than R,R,R-DHTBZ. Neither valbenazine, R,R,R-DHTBZ, nor NBI-136110 had significant off-target interactions at serotonin (5-HT1A, 5-HT2A, 5-HT2B) or dopamine (D1, or D2) 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-DHTBZ 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]).
- The American Society for Pharmacology and Experimental Therapeutics