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
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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
DrugTargetPropertyMeasurementpHTemperature (°C)
DesipramineSodium-dependent noradrenaline transporterKi (nM)2.1N/AN/ADetails
DesipramineSodium-dependent noradrenaline transporterIC 50 (nM)3.4N/AN/ADetails
FluoxetineSodium-dependent serotonin transporterIC 50 (nM)9.4N/AN/ADetails
VenlafaxineSodium-dependent noradrenaline transporterKi (nM)385N/AN/ADetails
VenlafaxineSodium-dependent noradrenaline transporterIC 50 (nM)535N/AN/ADetails
VenlafaxineSodium-dependent serotonin transporterIC 50 (nM)31N/AN/ADetails