Nisoxetine (developmental code name LY-94939), originally synthesized in the Lilly research laboratories during the early 1970s, is a potent and selective inhibitor for the reuptake of norepinephrine (noradrenaline) into synapses. It currently has no clinical applications in humans, although it was originally researched as an antidepressant. Nisoxetine is now widely used in scientific research as a standard selective norepinephrine reuptake inhibitor. It has been used to research obesity and energy balance, and exerts some local analgesia effects. Researchers have attempted to use a carbon-labeled form of nisoxetine for positron emission tomography (PET) imaging of the norepinephrine transporter (NET), with little success. However, it seems that tritium-labeled nisoxetine (3H-nisoxetine, 3H-NIS) is a useful radioligand for labeling norepinephrine uptake sites in vitro, which nisoxetine and other antagonists for NET are able to inhibit.
History In treating depression, it was theorized that substances that could enhance norepinephrine transmission, such as tricyclic antidepressants (TCA), could diminish the symptoms of clinical depression. The origins of nisoxetine can be found within the discovery of fluoxetine (Prozac, by Eli Lilly). In the 1970s, Bryan B. Molloy (a medicinal chemist) and Robert Rathbun (a pharmacologist) began a collaboration to search for potential antidepressant agents that would still retain the therapeutic activity of TCAs without undesirable cardiotoxicity and anticholinergic properties. The antihistamine drug diphenhydramine was found to inhibit monoamine uptake in addition to antagonizing histamine receptors, and this inhibition of monoamine uptake became a potential application for treating depression. As a result, Molloy, along with colleagues Schmiegal and Hauser, synthesized members of the phenoxyphenylpropylamine (PPA) group as analogues of diphenhydramine. Richard Kattau in the Rathbun laboratory tested the newly created drugs within the series of PPAs for their ability to reverse apomorphine-induced hypothermia in mice (PIHM), a test in which the TCAs were active antagonists. Kattau found that one member of the series, LY94939 (nisoxetine), was as potent and effective as the TCAs in the reversal of PIHM. Nisoxetine was found to be as potent as desipramine in inhibiting norepinephrine uptake in brain synaptosomes while not acting as a potent inhibitor of serotonin (5-HT) or dopamine uptake. Preclinical studies in humans were also performed in 1976 to evaluate the safety and possible mechanism of nisoxetine. At doses capable of blocking the uptake of norepinephrine and tyramine at nerve terminals, nisoxetine did not produce any substantial side effects. Abnormal electrocardiogram effects were also not observed, indicating it to be a relatively safe compound. Later, however, researchers considered ways in which subtle chemical differences in the PPA series could selectively inhibit 5-HT uptake, which eventually led to the synthesis of nisoxetine's 4-trifluoremethyl analogue, fluoxetine. Nisoxetine was never marketed as a drug due to a greater interest in pursuing the development of fluoxetine, a selective serotonin reuptake inhibitor (SSRI).
Research
Obesity Numerous evidence suggests that by altering catecholaminergic signaling (cell communication via norepinephrine and dopamine), food intake and body weight will be affected via classic hypothalamic systems that are involved in the regulation of energy balance. Antidepressants, such as the atypical antidepressant bupropion, can also cause weight loss due to their ability to increase extracellular dopamine and norepinephrine by inhibiting their uptake. Other research has focused on the interaction of serotonin and norepinephrine, leading to serotonin–norepinephrine reuptake inhibitors (SNRIs) as anti-obesity drugs. The primary forebrain sensor of peripheral cues that relays information about the availability of energy and storage is the arcuate nucleus of the hypothalamus (ARH), and it contains two types of cells that have opposing effects on energy balance. These two types of cells are neuropeptide Y (NPY)-expressing cells, which cause hyperphagia and energy conservation, and cells that pro-opiomelanocortin (POMC), which are related to hypophagia and increased energy expenditure. NPY and norepinephrine are both localized in select neurons in the brain and periphery. A norepinephrine reuptake inhibitor, such as nisoxetine, could potentially cause anorexia by decreasing activity of cells that express NPY and norepinephrine. In lean and obese mice, selective and combined norepinephrine and dopamine reuptake inhibition reduces food intake and body weight. Yet selective reuptake inhibitors of norepinephrine and dopamine (nisoxetine and a substance codenamed GBR12783, respectively) independently have no effect on food intake in mice. However, when given in combination, there is profound inhibition of food intake. This demonstrates a synergistic interaction between dopamine and norepinephrine in controlling ingestive behavior, similar to the action of SNRIs. The fact that nisoxetine alone does not affect food intake suggests that norepinephrine alone is insufficient to affect feeding or that the blocked reuptake of norepinephrine by nisoxetine is acting in the wrong place. Unlike nisoxetine, its sulfur analog thionisoxetine reduces food consumption in rodents and is a more promising treatment for obesity and eating disorders.
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