@article{7219e42926254f02bb530cf121b582c9,
title = "Stereoselective inhibition of serotonin re-uptake and phosphodiesterase by dual inhibitors as potential agents for depression",
abstract = "Multi-target compounds where more than one functional activity is incorporated into the same molecule may have advantages in treating disease states. Selective serotonin re-uptake inhibitors (SSRIs)a (i.e., (R)- and (S)-norfluoxetine) were chemically linked to a PDE4 inhibitor via a five carbon bridge. The new dual PDE4 inhibitor/SSRIs (i.e., (R)-8 and (S)-8) showed moderately potent but highly selective serotonin re-uptake inhibition (IC50 values of 173 and 42 nM, respectively) in vitro. The dual PDE4 inhibitor/SSRIs (R)-8 and (S)-8 also inhibited PDE4D2 (i.e., Ki values of 106 and 253 nM, respectively). Due to the synergistic functional activity, PDE4 inhibitor/SSRIs may be effective in treating diseases such as depression.",
keywords = "Depression, Dual selective serotonin re-uptake inhibitor/PDE4 inhibitor, Fluoxetine, Transporters",
author = "Cashman, {John R.} and Troy Voelker and Robert Johnson and Aaron Janowsky",
note = "Funding Information: The analytical help of Luke Guo and John Buza is gratefully acknowledged. The financial support of the HBRI is gratefully acknowledged. Funding Information: Chemicals used in this study were of the highest purity available. Commercially available reagents including (R)- and (S)-α,α,α-trifluoromethyl-p-cresol were purchased from Aldrich Chemical Company (Milwaukee, WI) or VWR (San Diego, CA) and were used as received. 2′-Fluo-AHC-cAMP was from Axxora LLC (San Diego, CA). All moisture sensitive reactions were carried out in flame-dried glassware under an argon atmosphere. Tetrahydrofuran (THF) and toluene were freshly distilled from calcium hydride under an argon atmosphere. Methanol (CH 3 OH) was passed through a column of neutral alumina and stored over 3 {\AA} molecular sieves prior to use. Fluoxetine was obtained from Sigma Chemical Company (St. Louis, MO). Cocaine was provided by the National Institute on Drug Abuse, NIH (Bethesda, MD). RTI-55 was a kind gift of Dr. Ivy Carroll (RTI, Research Triangle Park, NC). [ 3 H]-DA, [ 3 H]-5-HT, [ 3 H]-NE and [ 125 I]-RTI-55 were purchased from Perkin-Elmer Life Sciences (Boston, MA). The preparation of the hDAT used was described previously. 19 The hSERT cDNA and HEK cells transfected with hNET cDNA was generously supplied by Dr. Randy Blakely (Vanderbilt University, Nashville, TN). The IMAP{\texttrademark} TR-FRET Screening Express with Progressive Binding Kit was obtained from Molecular Devices (Sunnyvale, CA). PDE4D2 was purchased from BPS Biosciences (San Diego, CA). Analytical thin-layer chromatography (TLC) was done on K6F silica gel 60 {\AA} glass-backed plates from Whatman (Clifton, NJ). Compounds were detected using UV absorption at 254 nm and/or stained with I 2 (iodine). Flash chromatography was done on (60 {\AA}) pore silica gel from E. Merck (Darmstadt, Germany). 1 H NMR (300 MHz) spectra were determined on a Varian Mercury 300 instrument in the indicated solvent. Low resolution mass spectra (LRMS) were recorded on a Hitachi M8000. High resolution mass spectra (HRMS) were obtained with a Micromass LCT time of flight mass spectrometer at the University of Montana Mass Spectral Facility (Missoula, MT) using ESI. ",
year = "2009",
month = jan,
day = "1",
doi = "10.1016/j.bmc.2008.10.065",
language = "English (US)",
volume = "17",
pages = "337--343",
journal = "Bioorganic and Medicinal Chemistry",
issn = "0968-0896",
publisher = "Elsevier Limited",
number = "1",
}