6.16:
Drugs Affecting Neurotransmitter Synthesis
Certain drugs inhibit the key enzymes involved in neurotransmitter synthesis.
For instance, α-methyltyrosine blocks tyrosine hydroxylase, while carbidopa inhibits the dopa decarboxylase, essential for catecholamine synthesis.
A few drugs, like methyldopa, are taken up by the adrenergic neurons and converted to α-methylnoradrenaline, a false transmitter. This α-methylnoradrenaline is stored in the synaptic vesicles instead of noradrenaline.
Compared to noradrenaline, α-methylnoradrenaline has weaker effects on α1 -receptors but stronger effects on presynaptic α2-receptors. This triggers the inhibitory feedback mechanism, thus reducing neurotransmitter production and release.
Neurotoxins, such as 6-hydroxydopamine and MPTP, undergo selective reuptake at neuronal junctions. They are converted into reactive, toxic compounds that can destroy nerve terminals.
The prodrug droxidopa is converted by dopa decarboxylase to noradrenaline and potentiates sympathetic actions.
Agents that interfere with noradrenergic synthesis have limited clinical scope due to their "off-target" effects and high toxicity.
6.16:
Drugs Affecting Neurotransmitter Synthesis
Drugs affecting neurotransmitter synthesis can impact the adrenergic neuron and the synthesis of neurotransmitters. For example, α-methyltyrosine and carbidopa target specific enzymes involved in catecholamine synthesis. α-methyltyrosine inhibits the enzyme tyrosine hydroxylase, which converts tyrosine into dopamine. By blocking this enzyme, α-methyltyrosine reduces dopamine production and other catecholamines. Carbidopa, on the other hand, inhibits the enzyme dopa decarboxylase, which converts levodopa into dopamine. By blocking dopa decarboxylase, carbidopa increases the levels of levodopa that reach the brain, enhancing dopamine synthesis.
Another way drugs can impact neurotransmitter synthesis is by producing false transmitters. Methyldopa, for instance, is absorbed by adrenergic neurons and converted into α-methylnoradrenaline, a false transmitter. This compound displaces noradrenaline and alters receptor activation. It stimulates α1 adrenoceptors less effectively but activates presynaptic α2 receptors more efficiently, leading to an inhibitory feedback mechanism that reduces neurotransmitter production and release.
Certain neurotoxins, such as 6-hydroxydopamine and MPTP (1-methyl-4-phenyl-1,2,3,5-tetrahydropyridine), act as "Trojan horses" by being selectively taken up by neuronal junctions. Once inside, they transform reactive compounds that ultimately damage and destroy the nerve terminals—for example, 6-hydroxydopamine targets dopaminergic neurons, while MPTP affects dopaminergic and adrenergic neurons.
Additionally, a prodrug called droxidopa can cross the blood-brain barrier and is converted into noradrenaline by the enzyme dopa decarboxylase. This enhances sympathetic activity and can be used to treat conditions associated with low noradrenaline levels.
While drugs impacting neurotransmitter synthesis provide valuable insights into the modulation of adrenergic function, their clinical applications are often limited due to off-target effects and potential toxicity concerns.