Radafaxine

Radafaxine (developmental code GW-353,162; also known as (2S,3S)-hydroxybupropion or (S,S)-hydroxybupropion^[1]) is a norepinephrine–dopamine reuptake inhibitor (NDRI) which was under development by GlaxoSmithKline in the 2000s for a variety of different indications but was never marketed.^[2] These uses included treatment of restless legs syndrome, major depressive disorder, bipolar disorder, neuropathic pain, fibromyalgia, and obesity.^[2] Regulatory filing was planned for 2007,^[3] but development was discontinued in 2006 due to "poor test results".^[4]

Radafaxine

Clinical data
Other names	(S,S)-Hydroxybupropion; (2S,3S)-Hydroxybupropion; GW-353,162
Routes of administration	Oral
ATC code	none
Identifiers
IUPAC name (+)-(2S,3S)-2-(3-chlorophenyl)-3,5,5-trimethylmorpholin-2-ol
CAS Number	192374-14-4 Y HCl: 106083-71-0 Y
PubChem CID	9795056
ChemSpider	7970823 Y
UNII	Q47741214K HCl: SYD411HZ3S Y
ChEMBL	ChEMBL1172928 Y
CompTox Dashboard (EPA)	DTXSID501318447
Chemical and physical data
Formula	C13H18ClNO2
Molar mass	255.74 g·mol−1
3D model (JSmol)	Interactive image
SMILES Clc1cccc(c1)[C@]2(O)OCC(N[C@H]2C)(C)C
InChI InChI=1S/C13H18ClNO2/c1-9-13(16,17-8-12(2,3)15-9)10-5-4-6-11(14)7-10/h4-7,9,15-16H,8H2,1-3H3/t9-,13+/m0/s1 Y Key:RCOBKSKAZMVBHT-TVQRCGJNSA-N Y
NY (what is this?)  (verify)

Pharmacology

Pharmacodynamics

Radafaxine is described as a norepinephrine–dopamine reuptake inhibitor (NDRI). In contrast to bupropion, it appears to have a higher potency on inhibition of norepinephrine reuptake than on dopamine reuptake. Radafaxine has about 70% of the efficacy of bupropion in blocking dopamine reuptake, and 392% of efficacy in blocking norepinephrine reuptake, making it fairly selective for inhibiting the reuptake of norepinephrine over dopamine.^[5][6] This, according to GlaxoSmithKline, may account for the increased effect of radafaxine on pain and fatigue.^[7] At least one study suggests that radafaxine has a low abuse potential similar to bupropion.^[8]

Chemistry

Radafaxine is a potent metabolite of bupropion, the compound in GlaxoSmithKline's Wellbutrin. More specifically, hydroxybupropion is a major metabolite of bupropion that is further metabolized via an intramolecular cyclization to give radafaxine as the (2S,3S) isomer,^[9] as well as the corresponding (2R,3R) isomer isomer, which is less pharmacologically active as a monoamine reuptake inhibitor than radafaxine.^[10][11][12] Manifaxine (GW-320,659) was developed as an analogue of radafaxine and has been studied for the treatment of ADHD and obesity.^[13][14]

See also

• (2R,3R)-Hydroxybupropion
• 3-Chlorophenmetrazine
• Manifaxine