Viloxazine is a selective norepinephrine reuptake inhibitor that has a long history of clinical use in Europe as an antidepressant. An immediate-release formulation was approved for the treatment of depression in the UK in 1974, and was subsequently marketed there and in several European countries for 30 years with no major safety concerns. In April of 2021, the United States Food and Drug Administration (FDA) approved the use of viloxazine (QELBREE), developed by Supernus Pharmaceuticals, for the treatment of attention-deficit/hyperactivity disorder (ADHD) in pediatric and adult patients. Approval was based on positive results from a series of short-term phase III clinical trials in which viloxazine improved the severity of ADHD symptoms in children and adolescents with diagnosed ADHD. Viloxazine is available as extended-release capsules for once-daily oral administration.

Amitriptyline is a derivative of dibenzocycloheptadiene and a tricyclic antidepressant (TCA) and is mainly used to treat symptoms of depression. It works on the central nervous system (CNS) by inhibiting the membrane pump mechanism responsible for uptake of norepinephrine and serotonin in adrenergic and serotonergic neurons. Amitriptyline has been frequently used as an active comparator in clinical trials on newer antidepressants. It is rarely used as a first-line antidepressant nowadays due to its high degree of toxicity in overdose and generally poorer tolerability than the newer antidepressants.

Bicifadine (DOV-220075) is not a narcotic and is well-tolerated and, in preclinical studies, has been shown not to act at any opiate receptor, but inhibits monoamine neurotransmitter uptake by recombinant human transporters in vitro with a relative potency of norepinephrine:serotonin:dopamine of 1:2:17. Bicifadine was in Phase II clinical trial for pain caused by diabetic neuropathy, in addition, was in phase III clinical trial to treat Chronic Low Back Pain, but that studies were discontinued

Esreboxetine (PNU-165442G) is the (S,S)-(+)-enantiomer of antidepressant reboxetine, a selective norepinephrine reuptake inhibitor. The (S,S)-enantiomer is a more potent inhibitor of norepinephrine transporter than (R,R)-enantiomer. Esreboxetine was being developed by Pfizer, primarily for the treatment of fibromyalgia.

Nisoxetine, 3-(o-methoxyphenoxy)-3-phenyl-N-methyl-propyl-amine, is a most active and selective inhibitor of norepinephrine uptake, which was developed by Eli Lilly as an antidepressant drug. It was shown that nisoxetine dose-dependently reduced acute food intake and the additive effect of it was preserved in obese mice. In addition, was revealed that nisoxetine produced local but not systemic analgesia against cutaneous nociceptive stimuli in rodents. However, this drug has no clinical applications in humans.

Dasotraline, also known as SEP-225,289, is a serotonin-norepinephrine-dopamine reuptake inhibitor (SNDRI). It has an extended half-life (47-77 hours) that supports the potential for plasma concentrations yielding a continuous therapeutic effect over the 24-hour dosing interval at steady state. Dasotraline has shown a lower potential for abuse than methylphenidate in clinical testing. Dasotraline was discovered by Sunovion Pharmaceuticals Inc. and is currently in development to evaluate its use in treating ADHD in adults and children, and BED in adults in the United States. It has not been approved by the U.S. Food and Drug Administration (FDA) for the treatment of ADHD, BED or any other disorder.

SKF83959 is a benzodiazepine derivative which acts as an agonist of D1 receptor. Activation of D1 receptors by SKF83959 fails to stimulate adenylyl cyclase and inhibits the stimulation of adenylyl cyclase induced by dopamine but stimulates phosphatidylinositol 4,5-biphosphate hydrolysis in membranes of frontal cortex. SKF83959 was identified as a specific agonist for the heteromer D1/D2 complex. SKF83959 elicit anti-parkinsonism effects in monkeys and rodents. In lower concentrations, SKF83959 inhibits serotonin, norepinephrine and dopamine transporters and is an allosteric regulator of sigma 1 receptor. The compound has demonstrated activity in a preclinical model of depression.

Reserpic acid, a derivative of the antihypertensive drug reserpine, can inhibit norepinephrine uptake although it is much less effective than reserpine itself. Recently was shown, that reserpic acid possessed a strong binding to the pancreatic lipase, a major target for controlling the obesity.