- Targeting the FKBP51/GR/Hsp90 Complex to Identify Functionally Relevant Treatments for Depression and PTSD
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Genetic and epigenetic alterations in FK506-binding protein 5 (FKBP5) have been associated with increased risk for psychiatric disorders, including post-traumatic stress disorder (PTSD). Some of these common variants can increase the expression of FKBP5, the gene that encodes FKBP51. Excess FKBP51 promotes hypothalamic-pituitary-adrenal (HPA) axis dysregulation through altered glucocorticoid receptor (GR) signaling. Thus, we hypothesized that GR activity could be restored by perturbing FKBP51. Here, we screened 1280 pharmacologically active compounds and identified three compounds that rescued FKBP51-mediated suppression of GR activity without directly activating GR. One of the three compounds, benztropine mesylate, disrupted the association of FKBP51 with the GR/Hsp90 complex in vitro. Moreover, we show that removal of FKBP51 from this complex by benztropine restored GR localization in ex vivo brain slices and primary neurons from mice. In conclusion, we have identified a novel disruptor of the FKBP51/GR/Hsp90 complex. Targeting this complex may be a viable approach to developing treatments for disorders related to aberrant FKBP51 expression.
- Sabbagh, Jonathan J.,Cordova, Ricardo A.,Zheng, Dali,Criado-Marrero, Marangelie,Lemus, Andrea,Li, Pengfei,Baker, Jeremy D.,Nordhues, Bryce A.,Darling, April L.,Martinez-Licha, Carlos,Rutz, Daniel A.,Patel, Shreya,Buchner, Johannes,Leahy, James W.,Koren, John,Dickey, Chad A.,Blair, Laura J.
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p. 2288 - 2299
(2018/06/19)
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- Combinatorial synthesis of benztropine libraries and their evaluation as monoamine transporter inhibitors
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A combinatorial synthesis of benztropine analogues is presented. Radical azidonation of 3-benzyloxy-8-azabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester 3 to 3-(1-azidobenzyloxy)-8-azabicyclo[3.2.1]octane-8- carboxylic acid terf-butyl ester 4 was used as a key step in the synthesis. This step was optimized by adding 10% DMF to the reaction. Reaction of 4 with phenyl magnesium bromide followed by Boc removal and N-methylation gave benztropine 1. Reaction of five-component Grignard reagents with 4 was used to create a two-dimensional library of 25 N-normethylbenztropine analogues. Further reaction of this library with five alkyl bromides was carried out to create a three-dimensional library containing 125 compounds. Screening of the libraries towards binding and inhibition of uptake of the human dopamine (hDAT), serotonin (hSERT) and norepinephrine transporters (hNET) was carried out. None of the synthesized compounds were found to be stronger than benztropine, and none were selective for inhibition of binding over monoamine uptake.
- Pedersen, Hanne,Sinning, Steffen,Buelow, Anne,Wiborg, Ove,Falborg, Lise,Bols, Mikael
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p. 2861 - 2869
(2007/10/03)
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