Mechanism of Action of VMAT2 Inhibitors
VMAT2 inhibitors act by reversibly inhibiting the vesicular monoamine transporter 2, preventing the uptake of monoamines into synaptic vesicles and causing depletion of monoamine stores in nerve terminals. 1
Primary Mechanism
VMAT2 inhibitors function through a specific molecular mechanism:
Inhibition of VMAT2 Transporter: They bind to and inhibit the human vesicular monoamine transporter type 2 (VMAT2), which is responsible for packaging monoamine neurotransmitters (dopamine, serotonin, norepinephrine, and histamine) into synaptic vesicles 1, 2
Blockade of Monoamine Storage: By inhibiting VMAT2, these drugs prevent the uptake of cytosolic monoamines into synaptic vesicles, leading to depletion of monoamine stores 1
Reversible Binding: Unlike some other drugs affecting monoamine systems, VMAT2 inhibitors like tetrabenazine bind reversibly to VMAT2 (Ki ≈ 100 nM) 1
Structural Binding Mechanisms
Recent structural studies have revealed the precise binding mechanisms:
Tetrabenazine: Binds in a VMAT2-specific pocket and traps the transporter in an occluded state, locking VMAT2 in a lumen-facing conformation with an occluded gating lid that arrests the transport cycle 3, 4
Reserpine (another VMAT2 inhibitor): Occupies the substrate-binding pocket and locks VMAT2 in a cytoplasm-facing state, expanding the vestibule and blocking substrate access 3, 4
Active Metabolites
Dihydrotetrabenazine (HTBZ): The major circulating metabolites of tetrabenazine, α-HTBZ and β-HTBZ, exhibit high binding affinity to VMAT2 and contribute significantly to the therapeutic effect 1
Deutetrabenazine: A deuterated form of tetrabenazine that works through the same mechanism but with modified pharmacokinetics 5
Clinical Applications
VMAT2 inhibitors are used clinically for:
- Treatment of chorea associated with Huntington's disease 5
- Management of tardive dyskinesia 5
- Potential applications in neuroimaging for conditions like Parkinson's disease 2
Pharmacological Specificity
VMAT2 inhibitors show some selectivity for different monoamine systems, which contributes to their clinical effects and side effect profiles 2
While their primary mechanism is VMAT2 inhibition, some VMAT2 inhibitors may have additional weak binding to other receptors (e.g., tetrabenazine exhibits weak binding affinity at dopamine D2 receptors with Ki = 2100 nM) 1
Distinguishing Features from Other Drug Classes
Unlike direct receptor antagonists or reuptake inhibitors, VMAT2 inhibitors act presynaptically to reduce the amount of neurotransmitter available for release, representing a unique approach to modulating monoaminergic neurotransmission 6, 4.
Understanding this mechanism has led to the development of newer VMAT2 inhibitors with improved pharmacokinetic profiles, such as deutetrabenazine, which maintains the same mechanism of action but with potentially reduced side effects 5.