Norepinephrine releasing agent

A norepinephrine releasing agent (NRA), also known as an adrenergic releasing agent, is a catecholaminergic type of drug that induces the release of norepinephrine (noradrenaline) and epinephrine (adrenaline) from the pre-synaptic neuron into the synapse.^[1][2] This in turn leads to increased extracellular concentrations of norepinephrine and epinephrine therefore an increase in adrenergic neurotransmission.^[1][2][3][4]

A closely related type of drug is a norepinephrine reuptake inhibitor (NRI), for instance reboxetine.^[5][6] Another class of drugs that stimulates adrenergic activity is the adrenergic receptor agonist class.^[7]

NRAs, frequently as norepinephrine–dopamine releasing agents (NDRAs) rather than as selective NRAs, are used for a variety of clinical indications including the following:^[1][2][8][9]

• For the treatment of attention deficit hyperactivity disorder (ADHD) — e.g., amphetamine, dextroamphetamine, levoamphetamine, lisdexamfetamine, methamphetamine^[8][10]
• As anorectics in the treatment of obesity and binge-eating disorder — e.g., amphetamine, lisdexamfetamine, phentermine, benzphetamine, phenmetrazine, aminorex^[8][9][11]
• As wakefulness-promoting agents in the treatment of narcolepsy — e.g., amphetamine, methamphetamine^[9][12][13]
• As nasal decongestants and bronchodilators — e.g., levomethamphetamine, propylhexedrine, ephedrine, pseudoephedrine, phenylpropanolamine^[14][15][16]
• Miscellaneous – e.g., amantadine^[17][18]

They are also used as recreational drugs, though this is typically reserved only for those that also induce the release of dopamine and/or serotonin, for instance amphetamine, methamphetamine, MDMA, mephedrone, 4-methylaminorex, and MDAI, among others.^{[19][20][21][22]}

Cathine and cathinone are NRAs found naturally in Catha edulis.^[23][24] Ephedrine and pseudoephedrine are also found naturally in Ephedra sinica.^[23][24][25] Both of these plants are used medicinally (and recreationally as well regarding the former).^[23][24][25] The endogenous trace amines phenethylamine and tyramine are NRAs found in many animals, including humans.^[26][1][2]

Selective NRAs include ephedrine, pseudoephedrine, phenylpropanolamine, levomethamphetamine, and D-phenylalaninol.^{[1][2][25][27]} These drugs also release dopamine to a much lesser extent however (e.g., ~10- to 20-fold less potently).^{[1][2][25][27]} No highly selective NRAs are currently known.^[28] Among the most selective known NRAs is ephedrine, which had about 19-fold higher potency for inducing norepinephrine release over dopamine release in one study.^[28][29] Levomethamphetamine has shown about 15-fold higher potency in inducing norepinephrine release over dopamine release.^[27][29] D-Phenylalaninol has 13-fold higher potency in inducing norepinephrine release over dopamine release.^[27] In contrast to levomethamphetamine, levoamphetamine is an NDRA, with only about 3-fold preference for inducing norepinephrine release over dopamine release in one study (versus dextroamphetamine being roughly equipotent on norepinephrine and dopamine release in the same study).^[21] NRAs play a significant role in treating ADHD, obesity, narcolepsy, and as sympathomimetics by enhancing adrenergic signaling.^{[1][2][8][30]}

• Monoamine releasing agent
• Serotonin releasing agent
• Dopamine releasing agent
• Serotonin–norepinephrine releasing agent
• Norepinephrine–dopamine releasing agent
• Serotonin–norepinephrine–dopamine releasing agent

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