title: Neurochemical, pharmacokinetic, and behavioral effects of the novel selective serotonin reuptake inhibitor BMS-505130.
abstract: 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.
authors.affiliation: Department of Neuroscience Drug Discovery, Bristol-Myers Squibb, Mail Stop 3CD-449, 5 Research Parkway, Wallingford CT 06492, USA.
authors.forename: Matthew T
authors.initials: MT
authors.lastname: Taber
authors.forename: Robert N
authors.initials: RN
authors.lastname: Wright
authors.forename: Thaddeus F
authors.initials: TF
authors.lastname: Molski
authors.forename: Wendy J
authors.initials: WJ
authors.lastname: Clarke
authors.forename: Patrick J
authors.initials: PJ
authors.lastname: Brassil
authors.forename: Derek J
authors.initials: DJ
authors.lastname: Denhart
authors.forename: Ronald J
authors.initials: RJ
authors.lastname: Mattson
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Lodge
mesh_terms: D000284:Administration, Oral; D000818:Animals; D016466:CHO Cells; D002460:Cell Line; D006224:Cricetinae; D003521:Cyclopropanes; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D019417:Hindlimb Suspension / Q000379:methods*; D006801:Humans; D007211:Indoles / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology; D008297:Male; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D049990:Membrane Transport Modulators; D026901:Membrane Transport Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011485:Protein Binding / Q000187:drug effects / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D050486:Serotonin Plasma Membrane Transport Proteins; D017367:Selective Serotonin Reuptake Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology
chemical_list: D003521:Cyclopropanes; D007211:Indoles; D008562:Membrane Glycoproteins; D049990:Membrane Transport Modulators; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D050486:Serotonin Plasma Membrane Transport Proteins; D017367:Selective Serotonin Reuptake Inhibitors; C502839:2-(5-cyano-1H-indol-3-yl)-1-(N,N-dimethylaminomethyl)cyclopropane; C493230:SLC6A4 protein, human; C493231:Slc6a4 protein, mouse; C493232:Slc6a4 protein, rat