Characterization of thien-2-yl 1S,2R-milnacipran analogues as potent norepinephrine/serotonin transporter inhibitors for the treatment of neuropathic pain.
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Dyck B, Tamiya J, Jovic F, Pick RR, Bradbury MJ, O'Brien J, Wen J, Johns M, Madan A, Fleck BA, Foster AC, Li B, Zhang M, Tran JA, Vickers T, Grey J, Saunders J, Chen C
Characterization of thien-2-yl 1S,2R-milnacipran analogues as potent norepinephrine/serotonin transporter inhibitors for the treatment of neuropathic pain.
J Med Chem. 2008 Nov 27;51(22):7265-72. doi: 10.1021/jm8009537.
- PubMed ID
- 18954038 [ View in PubMed]
- Abstract
Thien-2-yl 1S,2R-milnacipran analogues were synthesized and characterized as norepinephrine/serotonin transporter inhibitors. These compounds possessed higher potencies than 1S,2R-milnacipran (2R-1) while maintaining low molecular weight and moderate lipophilicity, which are the important features for the pharmacological and pharmacokinetic characteristics of milnacipran (1). Thus, compound 5c exhibited IC50 values of 2.3 and 32 nM, respectively, at NET and SERT, which were more than 10-fold better than those of 1 (NET IC50 = 77 nM, SERT IC50 = 420 nM). Moreover, 5c achieved the same efficacy as 1, but with much lower doses, in a rodent spinal nerve ligation pain model. In addition, 5c displayed desirable pharmacokinetic properties in several species, including high oral availability and significant brain penetration.
DrugBank Data that Cites this Article
- Binding Properties
Drug Target Property Measurement pH Temperature (°C) Atomoxetine Sodium-dependent noradrenaline transporter IC 50 (nM) 5.1 N/A N/A Details Atomoxetine Sodium-dependent serotonin transporter IC 50 (nM) 190 N/A N/A Details Duloxetine Sodium-dependent dopamine transporter IC 50 (nM) 660 N/A N/A Details Duloxetine Sodium-dependent noradrenaline transporter IC 50 (nM) 8.9 N/A N/A Details Duloxetine Sodium-dependent serotonin transporter IC 50 (nM) 6.6 N/A N/A Details