Nisoxetine

Nisoxetine

Clinical data
ATC code	None
Legal status
Legal status	Never marketed
Identifiers
IUPAC name (RS)-3-(2-methoxyphenoxy)-N-methyl-3-phenylpropan-1-amine
Synonyms	LY-94939, (±)-γ-(2-Methoxyphenoxy)-N-methyl-benzenepropanamine hydrochloride
CAS Number	57226-61-6 Y
PubChem (CID)	4500
IUPHAR/BPS	4637
ChemSpider	4344 Y
UNII	17NV064B2D Y
KEGG	D05173 Y
ChEBI	CHEBI:73410 N
ChEMBL	CHEMBL295467 Y
Chemical and physical data
Formula	C17H21NO2
Molar mass	271.354 g/mol
3D model (Jmol)	Interactive image
Chirality	Racemic mixture
SMILES CNCCC(C1=CC=CC=C1)OC2=CC=CC=C2OC
InChI InChI=1S/C17H21NO2/c1-18-13-12-15(14-8-4-3-5-9-14)20-17-11-7-6-10-16(17)19-2/h3-11,15,18H,12-13H2,1-2H3 Y Key:ITJNARMNRKSWTA-UHFFFAOYSA-N Y
NY (what is this?)

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.

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.