A perhaps unexpected role of norepinephrine in actions of MDMA

Indirect-acting adrenergic agonists potentiate the effects of endogenous catecholamines through different mechanisms without directly binding to adrenoceptors.
One mechanism involves depleting stored catecholamines by displacing them from synaptic vesicles. These agents, known as "displacers," are transported into vesicles at the expense of noradrenaline. Examples include amphetamine and tyramine, which lack a catechol moiety, resulting in prolonged action, improved oral bioavailability, and...

Certain drugs can affect how neurotransmitters called catecholamines, are released or taken back up in the adrenergic neuron. They can have different effects on the body's sympathetic transmission. Reserpine, a natural compound found in the Rauwolfia shrub, blocks a transporter called vesicular monoamine transporter (VMAT), which leads to a buildup of catecholamines in the cell and reduces sympathetic transmission. Another drug called guanethidine works in multiple ways, including blocking...

Postganglionic sympathetic fibers (except those supplying the sweat glands) releasing noradrenaline or norepinephrine are called noradrenergic or adrenergic neurons. Noradrenaline, dopamine, adrenaline, or epinephrine are collectively called "catecholamines" as they contain a catechol moiety and an amine side chain. The five stages of neurotransmitter release involve their synthesis, storage, release, reuptake and metabolism.
Synthesis: Catecholamine synthesis requires tyrosine, which is taken...

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...

Mixed-action adrenergic agonists, like ephedrine and pseudoephedrine, directly and indirectly affect adrenergic receptors. These agents stimulate adrenoceptors and indirectly release stored neurotransmitters, amplifying the adrenergic response.
Ephedrine and pseudoephedrine lack a catecholamine group, making them less susceptible to degradation by metabolic enzymes. They have increased oral bioavailability and lipophilicity, resulting in a longer duration of action. Their response is reduced by...

Adrenergic agonists' structure-activity relationship (SAR) determines their selectivity and efficacy. These agonists comprise a phenylethylamine moiety with an aromatic ring and an ethylamine side chain.
Aromatic ring substitutions: Substituting the aromatic ring with –OH groups at positions 3 and 4 yields catecholamines (e.g., epinephrine), which have a high affinity for adrenoceptors. Hydrogen bonding between –OH groups and receptors enhances adrenergic activity.
Separation of the aromatic...