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A norepinephrine reuptake inhibitor (NRI, NERI) or adrenergic reuptake inhibitor (ARI), is a type of drug that acts as a reuptake inhibitor for the neurotransmitters norepinephrine (noradrenaline) and epinephrine (adrenaline) by blocking the action of the norepinephrine transporter (NET). This in turn leads to increased extracellular concentrations of norepinephrine and epinephrine and therefore can increase in adrenergic neurotransmission.

NRIs are commonly used in the treatment of conditions like ADHD and narcolepsy due to their psychostimulant effects and in obesity due to their appetite suppressant effects. They are also frequently used as antidepressants for the treatment of major depressive disorder, anxiety and panic disorder. Additionally, many drugs of abuse such as cocaine and methylphenidate possess NRI activity, though it is important to mention that NRIs without combined dopamine reuptake inhibitor (DRI) properties are not significantly rewarding and hence are considered to have a negligible abuse potential. However, norepinephrine has been implicated as acting synergistically with dopamine when actions on the two neurotransmitters are combined (e.g., in the case of NDRIs) to produce rewarding effects in psychostimulant drugs of abuse.

A meta analysis published in BMJ in 2011 concluded that the selective norepinephrine reuptake inhibitor reboxetine is indistinguishable from placebo in the treatment of depression. A second review by the European Medicines Agency concluded that reboxetine was significantly more effective than placebo, and that its risk/benefit ratio was positive. The latter review, also examined the efficacy of reboxetine as a function of baseline depression, and concluded that it was effective in severe depression and panic disorder but did not show effects significantly superior to placebo in mild depression.

A closely related type of drug is a norepinephrine releasing agent (NRA).

List of selective NRIs

Many NRIs exist, including the following:

• Pure norepinephrine reuptake inhibitors
  • Amedalin (UK-3540-1)
  • Atomoxetine (Strattera)
  • CP-39,332
  • Daledalin (UK-3557-15)
  • Edivoxetine (LY-2216684)
  • Esreboxetine
  • Lortalamine (LM-1404)
  • Nisoxetine (LY-94,939)
  • Reboxetine (Edronax, Vestra)
  • Talopram (Lu 3-010)
  • Talsupram (Lu 5-005)
  • Tandamine (AY-23,946)
  • Viloxazine (Vivalan)
• NRIs with activity at other sites
  • Bupropion (Wellbutrin, Zyban)
  • Ciclazindol (Wy-23,409)
  • Manifaxine (GW-320,659)
  • Maprotiline (Deprilept, Ludiomil, Psymion)
  • Radafaxine (GW-353,162)
  • Tapentadol (Nucynta)
  • Teniloxazine (Lucelan, Metatone)
  • NS8880 doi:10.1016/j.nucmedbio.2014.06.004
  • NS12137 doi:10.1016/j.nucmedbio.2017.10.005
  • Zhou J has also performed work into this area, e.g. Drugs Future. 2004 Dec;29(12):1235-1244.
  • F. Ivy Carroll also made an attempt at hegemony into selective NRI theory:
  • Certain tricyclic antidepressants are primarily norepinephrine reuptake inihibitors, with no clinically relevant serotonin reuptake except in rare cases where large doses are used. Protriptyline (Vivactil), Nortriptyline (Pamelor), and Desipramine (Norpramin) are examples of these.

Note: Only NRIs selective for the NET greater than the other two monoamine transporters (MATs) are listed here. For a list of NRIs that act at multiple MATs, see the other monoamine reuptake inhibitor pages such as NDRI, SNRI, and SNDRI.

See also

• Monoamine reuptake inhibitor

References

1. Wee S, Woolverton WL (September 2004). "Evaluation of the reinforcing effects of atomoxetine in monkeys: comparison to methylphenidate and desipramine". Drug and Alcohol Dependence. 75 (3): 271–6. doi:10.1016/j.drugalcdep.2004.03.010. PMID 15283948.
2. Gasior M, Bergman J, Kallman MJ, Paronis CA (April 2005). "Evaluation of the reinforcing effects of monoamine reuptake inhibitors under a concurrent schedule of food and i.v. drug delivery in rhesus monkeys". Neuropsychopharmacology. 30 (4): 758–64. doi:10.1038/sj.npp.1300593. PMID 15526000.
3. Rothman RB, Baumann MH, Dersch CM, et al. (January 2001). "Amphetamine-type central nervous system stimulants release norepinephrine more potently than they release dopamine and serotonin". Synapse. 39 (1): 32–41. doi:10.1002/1098-2396(20010101)39:1<32::AID-SYN5>3.0.CO;2-3. PMID 11071707.
4. Eyding D, Lelgemann M, Grouven U, et al. (2010). "Reboxetine for acute treatment of major depression: systematic review and meta-analysis of published and unpublished placebo and selective serotonin reuptake inhibitor controlled trials". BMJ. 341: c4737. doi:10.1136/bmj.c4737. PMC 2954275. PMID 20940209.
5. "MHRA Public Assessment Report" (PDF). Retrieved 2014-04-26.
6. Carroll, F. Ivy; Tyagi, Sameer; Blough, Bruce E.; Kuhar, Michael J.; Navarro, Hernn A. (2005). "Synthesis and Monoamine Transporter Binding Properties of 3α-(Substituted phenyl)nortropane-2β-carboxylic Acid Methyl Esters. Norepinephrine Transporter Selective Compounds". Journal of Medicinal Chemistry. 48 (11): 3852–3857. doi:10.1021/jm058164j. ISSN 0022-2623.

• Norepinephrine reuptake inhibitors