DBH Inhibitors

Dopamine β-hydroxylase (DBH) inhibitors are a diverse group of compounds that attenuate the activity of DBH, a copper-containing enzyme that catalyzes the conversion of dopamine to norepinephrine. They accomplish this through a variety of direct and indirect mechanisms. Direct inhibitors like Disulfiram, Nepicastat, Etamicastat, Tolcaperone, and Fusaric Acid bind to the active site of DBH, preventing it from catalyzing its target reaction. Disulfiram and Fusaric Acid, for instance, bind to the copper active site of DBH, thereby impeding its function. On the other hand, indirect inhibitors such as Metyrosine, Reserpine, Tetrabenazine, Carbidopa, α-methyltyrosine, Phenelzine, and Deprenyl (Selegiline) influence DBH activity by modulating related biochemical pathways or cellular processes. For example, Metyrosine and α-methyltyrosine inhibit tyrosine hydroxylase, the rate-limiting enzyme in catecholamine synthesis. This action decreases the pool of dopamine available, thus indirectly reducing DBH activity. Similarly, Carbidopa inhibits aromatic L-amino acid decarboxylase, which also leads to a reduction in dopamine availability.Reserpine and Tetrabenazine operate by inhibiting the vesicular monoamine transporter (VMAT), which is responsible for packaging dopamine into vesicles for subsequent conversion to norepinephrine by DBH. By depleting these stores of dopamine, these inhibitors indirectly reduce the need for DBH activity. Finally, Phenelzine and Deprenyl (Selegiline) inhibit monoamine oxidase, which is involved in the breakdown of monoamines. By increasing the levels of these monoamines, they indirectly reduce the need for DBH activity. Within the class of DBH inhibitors, there are also differences in their reversibility and selectivity. For instance, Disulfiram is an irreversible inhibitor, while Etamicastat and Tolcaperone are reversible. This difference can have significant implications for the duration and extent of DBH inhibition. Selectivity is another important factor. Nepicastat, for example, is a selective DBH inhibitor, meaning it primarily inhibits DBH without significantly affecting other enzymes. On the other hand, Disulfiram inhibits not only DBH but also aldehyde dehydrogenase.