|
Nisoxetine, 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 anticholingergic 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, 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 apomorphine-induced hypothermia in mice.〔〔 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).〔 抄文引用元・出典: フリー百科事典『 ウィキペディア（Wikipedia）』 ■ウィキペディアで「Nisoxetine」の詳細全文を読む スポンサード リンク
|