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Biological characterization of THRX‐956485, a peripherally‐selective serotonin transport reuptake inhibitor
Author(s) -
McConn Donavon,
Tsuruda Pamela,
McNamara Alexander,
Hegde Sharath,
Stangeland Eric
Publication year - 2012
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.26.1_supplement.lb538
Subject(s) - serotonin , serotonin reuptake inhibitor , serotonin transporter , pharmacology , fluoxetine , reuptake inhibitor , reuptake , chemistry , serotonin plasma membrane transport proteins , serotonin uptake inhibitors , ex vivo , citalopram , endocrinology , medicine , receptor , in vitro , biochemistry
Peripheral serotonin has been implicated in many therapeutic indications including thrombosis, pulmonary hypertension and osteoporosis. A peripheral selective serotonin reuptake inhibitor (SSRI) without CNS activity could provide a therapeutic index exceeding standard SSRIs. We describe a novel compound that selectively inhibits peripheral serotonin reuptake. THRX‐956485 is a potent (hSERT uptake IC 50 /binding K i = 2.5nM/1.0nM) and selective SERT inhibitor in vitro and is >2500‐ fold selective over other reuptake transporters and serotonin receptors. In rat PK studies (single 5 mg/kg PO), or 14‐day osmotic mini‐pump infusions (0.3, 0.7 and 1.6 mg/kg/day), THRX‐956485 showed pronounced peripheral selectivity compared to a CNS‐penetrant SSRI, fluoxetine. Based on unbound CNS vs. plasma exposures and measured SERT occupancy ex vivo , THRX‐ 956485 was >20‐fold peripherally selective (CSF:unbound plasma concentration ratios varied from 1–5%). Additionally, THRX‐956485 demonstrated a dose‐dependent reduction in blood serotonin concentrations in rats. Following 14‐day infusions, blood serotonin concentrations decreased from 94 ng/mL (vehicle) to 43, 25, and 11 ng/mL at 0.3, 0.7 and 1.6 mg/kg/day, respectively. These findings are consistent with inhibition of platelet serotonin uptake, and suggest that THRX‐956485 is a peripherally selective SSRI.