Neurochemical, pharmacokinetic, and behavioral effects of the novel selective serotonin reuptake inhibitor BMS-505130.

BMS-505130 is a potent and selective serotonin transport inhibitor; K(i) for binding to the serotonin transporter = 0.18 nM (K(i) values for binding to the norepinephrine and dopamine transporters = 4.6 and 2.1 microM, respectively). In platelet serotonin uptake studies BMS-505130 (5 mg/kg, p.o.) produced a robust inhibition of serotonin uptake. In microdialysis studies oral dosing with BMS-505130 produced a dose-dependent increase in cortical serotonin levels that reached a maximal effect of 200% above baseline at a dose of 1 mg/kg, p.o.; the peak serotonin response was transient in nature. Following oral administration, peak plasma concentrations of BMS-505130 reached Tmax at 1.6 +/- 0.7 h and then declined to concentrations <10% of Cmax within the following 6 h; plasma half-life following i.v. dosing was 0.46 +/- 0.02 h. Parallel microdialysis and pharmacokinetic studies revealed that changes in serotonin levels in the cortex mirrored changes in the brain concentration of BMS-505130. In a behavioral assay known to be sensitive to selective serotonin reuptake inhibitors (SSRIs), mouse tail suspension, BMS-505130 produced a robust response after either oral or intraperitoneal dosing. BMS-505130 exhibits a pharmacological, neurochemical and behavioral profile consistent with a potent SSRI. Moreover, BMS-505130's short half-life may be advantageous for the treatment of premature ejaculation where an acute effect to delay ejaculation followed by a relatively rapid fall in SSRI plasma concentrations might be desirable.