Identification of 1S,2R-milnacipran analogs as potent norepinephrine and serotonin transporter inhibitors

Tamiya, Junko; Dyck, Brian; Zhang, Mingzhu; Phan, Kasey; Fleck, Beth A.; Aparicio, Anna; Jovic, Florence; Tran, Jennifer; Vickers, Troy; Grey, Jonathan; Foster, Alan C.; Chen, Chen

doi:10.1016/j.bmcl.2008.04.025

Cited by 18 publications

(10 citation statements)

References 23 publications

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“…In these studies, primarily the phenyl ring and the tertiary amino moiety have been modified, and these structural modifications have led to increased potency towards both SERT and NET, and the SNRI profile has generally been retained. [77][78][79][80] However, in some cases a modified selectivity profile was achieved. Substitution of one of the N-ethyl groups in milnacipran ( 21) for an N-phenyl group (35) selectively decreased the activity towards SERT leading to 100-fold selectivity for NET over SERT (Fig.…”

Section: Venlafaxine and Desvenlafaxinementioning

confidence: 99%

Recent advances in the understanding of the interaction of antidepressant drugs with serotonin and norepinephrine transporters

et al. 2009

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The biogenic monoamine transporters are integral membrane proteins that perform active transport of extracellular dopamine, serotonin and norepinephrine into cells. These transporters are targets for therapeutic agents such as antidepressants, as well as addictive substances such as cocaine and amphetamine. Seminal advances in the understanding of the structure and function of this transporter family have recently been accomplished by structural studies of a bacterial transporter, as well as medicinal chemistry and pharmacological studies of mammalian transporters. This feature article focuses on antidepressant drugs that act on the serotonin and/or the norepinephrine transporters. Specifically, we focus on structure-activity relationships of these drugs with emphasis on relationships between their molecular properties and the current knowledge of transporter structure.

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Section: Venlafaxine and Desvenlafaxinementioning

confidence: 99%

Recent advances in the understanding of the interaction of antidepressant drugs with serotonin and norepinephrine transporters

et al. 2009

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“…It is a more balanced reuptake inhibitor of serotonin and norepinephrine than other SNRIs . Substituted milnacipran analogues have shown promising pharmaceutical properties and are interesting target molecules in drug development . Several routes have been identified for the preparation of levominacipran 1 .…”

Section: Introductionmentioning

confidence: 99%

Toward a Large-Scale Approach to Milnacipran Analogues Using Diazo Compounds in Flow Chemistry

Mueller

Murat

Hellier

et al. 2015

Org. Process Res. Dev.

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The safe use of diazo reagents for the preparation of a key structure in the synthesis of milnacipran analogues is described herein. Using continuous flow technology, the diazo reagent is synthesized, purified, dried, and subsequently used in semi-batch mode for an intramolecular cyclopropanation. Side products formed in the reaction are isolated and rationalized to optimize the process. Different separation techniques in flow are compared with regard to their ability to produce pure and dry diazo reagents. The studies yield a scalable process to a key intermediate in the syntheses of milnacipran and its possible substituted analogues.

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“…10 In vitro studies have demonstrated that levomilnacipran inhibits the norepinephrine transporter with 2-fold higher potency than the serotonin transporter, based on the half-maximal inhibitory concentration (IC50) of drug administered (IC50 = 10.5 nM [NE] and 19.0 nM [5HT]; NE/5HT ratio = 0.6). 10,20 An in vitro study utilizing Chinese Hamster Ovary Cells transfected with human serotonin and norepinephrine transporters found that levomilnacipran's reuptake inhibition of both norepinephrine and serotonin occurred in a concentration-dependent manner. 10 At the lowest effective dose (10 mg/kg), levomilnacipran exhibits greater activity for norepinephrine, and as the dosage is increased to 20 and 40 mg/kg, it displays equivalent activities for norepinephrine and serotonin.…”

Section: Pharmacologymentioning

confidence: 99%

Section: Pharmacologymentioning

confidence: 99%

Levomilnacipran

2014

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Levomilnacipran demonstrates efficacy and tolerability for short-term treatment of MDD in adults. Available evidence does not strongly indicate that there is a specific subpopulation of patients who would benefit from levomilnacipran over currently available SNRIs. Full characterization of the agent's place in therapy alongside multiple other agents with similar mechanisms and efficacy requires trials with longer duration and active comparators.

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Identification of 1S,2R-milnacipran analogs as potent norepinephrine and serotonin transporter inhibitors

Cited by 18 publications

References 23 publications

Recent advances in the understanding of the interaction of antidepressant drugs with serotonin and norepinephrine transporters

Recent advances in the understanding of the interaction of antidepressant drugs with serotonin and norepinephrine transporters

Toward a Large-Scale Approach to Milnacipran Analogues Using Diazo Compounds in Flow Chemistry

Levomilnacipran

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