Buy Manifaxine (GW-320-659) Cas 135306-39-7
Buy Manifaxine (GW-320-659) Cas 135306-39-7
Buy Manifaxine (GW-320-659) Cas 135306-39-7
Manifaxine (developmental code name GW-320,659) is a norepinephrine–dopamine reuptake inhibitor developed by GlaxoSmithKline through structural modification of radafaxine, an isomer of hydroxybupropion and one of the active metabolites of bupropion.[1] Manifaxine was researched for treatment of attention deficit hyperactivity disorder (ADHD) and obesity and was found to be safe, reasonably effective, and well-tolerated for both applications.[2][3] However, no results were reported following these initial trials and development was discontinued.[1]
Synthesis
The Grignard reaction between 3,5-difluorobenzonitrile (1) and ethylmagnesium bromide gives 3,5-difluoropropiophenone (2). Halogenation with molecular bromine occurs at the alpha-keto position providing 2-bromo-3′,5′-difluoropropiophenone (3). Intermolecular ring formation with DL-alaninol (2-aminopropanol) completes the synthesis of manifaxine (4).
See also
-
Manifaxine (CAS 135306-39-7) | Selective NDRI InhibitorManifaxine: Selective NDRI for ADHD & Obesity Manifaxine (developmental code GW320659; also BW1555U88) is a synthetic, chiral 2-ph…
Manifaxine
MANIFAXINE HYDROCHLORIDE – Inxight Drugs
Manifaxine
Content Navigation
Bupropion requires CYP2B6 metabolism for activity, causing inconsistent in vitro NDRI assays, while its unfluorinated metabolite radafaxine shows lower lipophilicity and reduced target binding. Manifaxine (CAS 135306-39-7) overcomes these limitations as a pre-cyclized, highly potent morpholine NDRI that directly engages norepinephrine and dopamine transporters without metabolic activation.
- Direct-acting positive control for novel NDRI screening.
- Pre-cyclized stability ensures reproducible receptor engagement.
- ≥98% purity, global shipping from research stock.
CAS Number
Product Name
IUPAC Name
Molecular Formula
Molecular Weight
InChI
InChI Key
SMILES
solubility
Synonyms
Canonical SMILES
Isomeric SMILES
Purity
Package Size
Manifaxine (CAS 135306-39-7) is a highly potent, direct-acting norepinephrine-dopamine reuptake inhibitor (NDRI) defined by its (2S,3S,5R)-2-(3,5-difluorophenyl)-3,5-dimethylmorpholin-2-ol structure [1]. Unlike earlier-generation aminoketones, this compound features a stabilized morpholine acetal ring and a 3,5-difluorophenyl substitution that imparts distinct amphiphilic properties, high solubility in polar aprotic solvents like DMSO, and predictable pH-dependent aqueous dissolution. For pharmacological research and synthetic assay development, Manifaxine serves as a high-purity, pre-cyclized benchmark, bypassing the complex in vivo metabolic activation required by standard cathinone-derived precursors[2].
Research Fit
Substituting Manifaxine with the more common benchmark bupropion or its unfluorinated metabolite radafaxine severely compromises in vitro assay precision [1]. Bupropion is heavily reliant on hepatic metabolism (primarily via CYP2B6) to form its active morpholinol metabolites, meaning its direct in vitro application often yields artificially low binding affinities and fails to replicate physiological NDRI activity [1]. Furthermore, the absence of the 3,5-difluoro substitution in radafaxine results in lower lipophilicity and reduced target binding efficiency[2]. Procuring Manifaxine ensures researchers have a pre-cyclized, metabolically stable, and highly potent morpholine scaffold that delivers immediate, quantifiable receptor engagement without requiring metabolic simulation.
Substitution Risk
Potent Norepinephrine Uptake Inhibition
Manifaxine demonstrates substantially higher affinity for the norepinephrine transporter compared to the baseline standard bupropion. The integration of the morpholine acetal structure and difluorophenyl motif provides additional hydrogen bonding and hydrophobic interactions, driving a 30-fold increase in in vitro NET inhibition activity [1].
| Evidence Dimension | In vitro Norepinephrine (NE) uptake inhibition potency |
| Target Compound Data | 30-fold higher activity |
| Comparator Or Baseline | Bupropion (Baseline aminoketone) |
| Quantified Difference | 30x greater in vitro potency |
| Conditions | In vitro monoamine uptake assay |
Essential for high-throughput screening and receptor binding assays where maximum direct target engagement is required without relying on metabolic activation.
In Vivo Monoamine Modulation
Beyond its in vitro binding superiority, Manifaxine maintains a robust translational advantage in systemic models. Compared to bupropion, Manifaxine exhibits a 4-fold higher in vivo activity for norepinephrine uptake inhibition [1]. This is attributed to the optimized lipophilicity and metabolic stability conferred by the 3,5-difluorophenyl group, which enhances central nervous system penetrance and target residence time.
| Evidence Dimension | In vivo Norepinephrine uptake inhibition |
| Target Compound Data | 4-fold higher activity |
| Comparator Or Baseline | Bupropion |
| Quantified Difference | 4x greater in vivo potency |
| Conditions | In vivo preclinical monoamine uptake models |
Allows researchers to use lower dosing thresholds in animal models, reducing off-target toxicity while achieving robust NDRI effects.
Pre-Cyclized Morpholine Stability
Bupropion exists as an aminoketone that undergoes intramolecular cyclization in vivo to form active morpholinols like hydroxybupropion and radafaxine[1]. Manifaxine is synthesized as a pre-cyclized, stereospecific (2S,3S,5R) morpholin-2-ol. This locked conformation prevents the spontaneous degradation or equilibrium shifts often seen in uncyclized cathinone derivatives under aqueous assay conditions, ensuring consistent molarity and reproducible binding kinetics across varied pH environments [1].
| Evidence Dimension | Structural conformation in aqueous media |
| Target Compound Data | Stable, pre-cyclized morpholine acetal |
| Comparator Or Baseline | Bupropion (uncyclized aminoketone subject to equilibrium/metabolism) |
| Quantified Difference | Elimination of metabolic dependency for active conformation |
| Conditions | Aqueous physiological buffers (pH 7.4) |
Guarantees that the exact molar concentration applied in an assay directly correlates to the active pharmacophore, eliminating the variability of spontaneous cyclization.
High-Throughput Monoamine Transporter Assays
Due to its 30-fold higher in vitro potency over bupropion and its pre-cyclized stability, Manifaxine is the optimal positive control for screening novel NDRI candidates in cell-based assays [1].
Preclinical Pharmacokinetic Modeling
Its metabolically stable, fluorinated morpholine structure makes it an ideal reference standard for LC-MS/MS studies mapping the CNS penetrance and half-life of advanced monoamine modulators [2].
Scaffold Derivatization in Medicinal Chemistry
The 3,5-difluorophenyl morpholinol core serves as an advanced starting material or benchmark for synthesizing next-generation treatments for neurological disorders, bypassing the metabolic liabilities of cathinone-based precursors [1].
Application Fit Matrix
XLogP3
Hydrogen Bond Acceptor Count
Hydrogen Bond Donor Count
Exact Mass
Monoisotopic Mass
Heavy Atom Count
Appearance
Storage
UNII
Other CAS
Wikipedia
Manifaxine
Manifaxine is a discontinued Phase II NDRI with no commercial pharmaceutical source, limiting access for pharmacogenetic obesity and ADHD research.
• NET IC50 0.07 µM, DAT IC50 1.0 µM; ~30-fold greater NE uptake inhibition than bupropion
• Genotype-stratified weight loss of 7.84 kg in SLC6A2/GRIN1 favorable polymorphism carriers (Phase II OBS20001)
• No off-target activity at SERT, adrenergic, dopaminergic, or serotonergic receptors at 10 µM
Ideal as a benchmark 2-phenylmorpholinol reference for SAR campaigns and genotype-stratified obesity proof-of-concept studies.
Technical Parameters
Basic Identity
| Product Name | Manifaxine |
|---|---|
| CAS | 135306-39-7 |
| Synonyms |
BW-1555U-88, GW-320659, 1555U-88, BW1555U88, GW320659, 1555U88, BW 1555U 88, GW 320659, 1555U 88
|
| Molecular Formula | C12H15F2NO2 |
| Molecular Weight | 243.25 g/mol |
Structural Identifiers
| SMILES | CC1COC(C(N1)C)(C2=CC(=CC(=C2)F)F)O |
|---|---|
| InChI | InChI=1S/C12H15F2NO2/c1-7-6-17-12(16,8(2)15-7)9-3-10(13)5-11(14)4-9/h3-5,7-8,15-16H,6H2,1-2H3/t7-,8+,12-/m1/s1 |
| InChIKey | OZGPVYJHWWPEFT-RGNHYFCHSA-N |
Commercial & Availability
| Standard Pack Sizes | 25 mg / 50 mg / 100 mg / 500 mg / Bulk Custom |
|---|---|
| Availability | In Stock |
| Custom Synthesis | Available on request |
Handling Information
| Appearance | Solid powder |
|---|---|
| Solubility | Soluble in DMSO |
| Storage | Dry, dark and at 0 – 4 C for short term (days to weeks) or -20 C for long term (months to years). |
Structure & Identifiers
Manifaxine: Selective NDRI for ADHD & Obesity
Manifaxine (developmental code GW320659; also BW1555U88) is a synthetic, chiral 2-phenylmorpholinol that acts as a highly selective neuronal norepinephrine–dopamine reuptake inhibitor (NDRI) . Originally developed by GlaxoSmithKline, it was advanced to Phase II clinical trials for attention‑deficit/hyperactivity disorder (ADHD) and obesity before being discontinued . Its chemical structure places it within a lineage of NDRIs that includes bupropion and its active metabolite radafaxine, yet Manifaxine was specifically optimized for enhanced norepinephrine transporter (NET) potency and selectivity over serotonergic targets . The compound is currently available exclusively for laboratory research and preclinical investigation through specialty chemical suppliers .
Why Generic NDRIs Cannot Replace Manifaxine
Although Manifaxine, bupropion, and radafaxine all inhibit norepinephrine and dopamine reuptake, their pharmacological profiles differ substantially in potency, in vivo efficacy, and pharmacogenetic response determinants. Manifaxine was engineered through rational structural modification of radafaxine to achieve approximately 30‑fold greater norepinephrine uptake inhibition potency than bupropion . This translates into distinct in vivo pharmacodynamic effects—Manifaxine is active in the anti‑tetrabenazine antidepressant model at doses where bupropion shows no efficacy . Furthermore, clinical trial data reveal that weight‑loss response to Manifaxine is strongly modulated by common polymorphisms in SLC6A2 and GRIN1, with a pharmacogenetically stratified subgroup losing 7.84 kg versus 2.53 kg in non‑stratified patients . Such genotype‑dependent efficacy has not been demonstrated for bupropion in obesity, indicating that Manifaxine engages a therapeutically exploitable pharmacogenetic mechanism. These quantitative differences mean that substituting a generic NDRI cannot replicate the potency, in vivo profile, or patient‑stratification potential that define Manifaxine as a distinct research compound.
Reviews
There are no reviews yet.