Abstract
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, (+)-α-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 [3H]-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 (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-HTBZ. Neither valbenazine, R,R,R-HTBZ, 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-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)].
Highlights
Dysregulation of dopaminergic neurotransmission is a key component of many central nervous system disorders, including hyperkinetic movement disorders such as tardive dyskinesia (TD) (Muller, 2015)
VBZ and NBI-136110 had similar effects on vesicular monoamine transporter 2 (VMAT2) inhibition, but with Ki values that were approximately 40–65 times the Ki values of R,R,R-HTBZ. These results were corroborated by the radioligand-binding assay of HTBZ stereoisomers (i.e., TBZ metabolites) in the rat forebrain, which showed R,R,R-HTBZ to be the most potent inhibitor of VMAT2, followed by S,R,R-HTBZ (Table 2)
Involuntary hyperkinetic dyskinesias, which can result from exposure to dopamine receptor–blocking agent (DRBA), are a serious limiting factor for chronic antipsychotic drug therapy (Youssef and Waddington, 1987; Browne et al, 1996; Ballesteros et al, 2000)
Summary
Dysregulation of dopaminergic neurotransmission is a key component of many central nervous system disorders, including hyperkinetic movement disorders such as tardive dyskinesia (TD) (Muller, 2015).
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