Structure-activity relationships of the cycloalkanol ethylamine scaffold: discovery of selective norepinephrine reuptake inhibitors.
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Mahaney PE, Gavrin LK, Trybulski EJ, Stack GP, Vu TA, Cohn ST, Ye F, Belardi JK, Santilli AA, Sabatucci JP, Leiter J, Johnston GH, Bray JA, Burroughs KD, Cosmi SA, Leventhal L, Koury EJ, Zhang Y, Mugford CA, Ho DM, Rosenzweig-Lipson SJ, Platt B, Smith VA, Deecher DC
Structure-activity relationships of the cycloalkanol ethylamine scaffold: discovery of selective norepinephrine reuptake inhibitors.
J Med Chem. 2008 Jul 10;51(13):4038-49. doi: 10.1021/jm8002262. Epub 2008 Jun 17.
- PubMed ID
- 18557608 [ View in PubMed]
- Abstract
Further exploration of the cycloalkanol ethylamine scaffold, of which venlafaxine ( 1) is a member, was undertaken to develop novel and selective norepinephrine reuptake inhibitors (NRIs) for evaluation in a variety of predictive animal models. These efforts led to the discovery of a piperazine-containing analogue, 17g (WY-46824), that exhibited potent norepinephrine reuptake inhibition, excellent selectivity over the serotonin transporter, but no selectivity over the dopamine transporter. Synthesis and testing of a series of cyclohexanol ethylpiperazines identified ( S)-(-)- 17i (WAY-256805), a potent norepinephrine reuptake inhibitor (IC 50 = 82 nM, K i = 50 nM) that exhibited excellent selectivity over both the serotonin and dopamine transporters and was efficacious in animal models of depression, pain, and thermoregulatory dysfunction.
DrugBank Data that Cites this Article
- Binding Properties
Drug Target Property Measurement pH Temperature (°C) Desipramine Sodium-dependent noradrenaline transporter Ki (nM) 2.1 N/A N/A Details Desipramine Sodium-dependent noradrenaline transporter IC 50 (nM) 3.4 N/A N/A Details Fluoxetine Sodium-dependent serotonin transporter IC 50 (nM) 9.4 N/A N/A Details Venlafaxine Sodium-dependent noradrenaline transporter Ki (nM) 385 N/A N/A Details Venlafaxine Sodium-dependent noradrenaline transporter IC 50 (nM) 535 N/A N/A Details Venlafaxine Sodium-dependent serotonin transporter IC 50 (nM) 31 N/A N/A Details