51. Characterization of thien-2-yl 1S,2R-milnacipran analogues as potent norepinephrine/serotonin transporter inhibitors for the treatment of neuropathic pain
- Author
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Mingzhu Zhang, Florence Jovic, Michael Johns, Troy Vickers, Joe A. Tran, Bin-Feng Li, Julie O'Brien, Margaret J. Bradbury, Jenny Wen, Rebecca R. Pick, John Saunders, Beth A. Fleck, Brian Dyck, Junko Tamiya, Alan C. Foster, Ajay Madan, Chen Chen, and Jonathan Grey
- Subjects
Cyclopropanes ,Male ,Models, Molecular ,Analgesic ,Administration, Oral ,Biological Availability ,Pharmacology ,Crystallography, X-Ray ,Rats, Sprague-Dawley ,chemistry.chemical_compound ,Structure-Activity Relationship ,Milnacipran ,Drug Discovery ,medicine ,Animals ,Humans ,Neurotransmitter ,Serotonin transporter ,Pain Measurement ,Serotonin Plasma Membrane Transport Proteins ,Norepinephrine Plasma Membrane Transport Proteins ,biology ,Dose-Response Relationship, Drug ,Molecular Structure ,Stereoisomerism ,Rats ,Molecular Weight ,Disease Models, Animal ,Spinal Nerves ,Biochemistry ,chemistry ,Drug Design ,Neuropathic pain ,Lipophilicity ,biology.protein ,Microsomes, Liver ,Molecular Medicine ,Neuralgia ,Serotonin ,Caco-2 Cells ,Reuptake inhibitor ,Selective Serotonin Reuptake Inhibitors ,medicine.drug - 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.
- Published
- 2008