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Eur J Med Chem. 2015 Mar 26;93:392-400. doi: 10.1016/j.ejmech.2015.02.004. Epub 2015 Feb 7.

Ether analogues of DPA-714 with subnanomolar affinity for the translocator protein (TSPO).

Author information

1
Department of Radiology, Stanford University School of Medicine, Stanford, CA 94305, USA; School of Chemistry, The University of Sydney, Sydney, NSW 2006, Australia.
2
School of Chemistry, The University of Sydney, Sydney, NSW 2006, Australia.
3
Department of Radiology, Stanford University School of Medicine, Stanford, CA 94305, USA.
4
Department of Pharmaceutical Sciences, University of Florence, Via U. Schiff, 650019 Polo Scientifico Sesto Fiorentino, Italy.
5
Department of Pharmacy, University of Pisa, Via Bonanno 6, 56127 Pisa, Italy.
6
School of Chemistry, The University of Sydney, Sydney, NSW 2006, Australia; Faculty of Health Sciences, The University of Sydney, Sydney, NSW 2006, Australia. Electronic address: michael.kassiou@sydney.edu.au.

Abstract

Sixteen new phenyl alkyl ether derivatives (12, 14-28) of the 5,7-dimethylpyrazolo[1,5-a]pyrimidin-3-ylacetamide (DPA) class were synthesized and evaluated in a competition binding assay against [(3)H]PK11195 using 18 kDa translocator protein (TSPO) derived from rat kidney mitochondrial fractions. All analogues showed superior binding affinities for TSPO compared to DPA-713 (5) and DPA-714 (6). Picomolar affinities were observed for this class of TSPO ligands in this assay for the first time, with phenethyl ether 28 showing the greatest affinity (Ki = 0.13 nM). Additionally, all analogues increased pregnenolone biosynthesis (134-331% above baseline) in a rat C6 glioma cell steroidogenesis assay.

KEYWORDS:

DPA-714; Positron emission tomography; Pyrazolo[1,5-a]pyrimidine; Steroid; Translocator protein

PMID:
25725375
DOI:
10.1016/j.ejmech.2015.02.004
[Indexed for MEDLINE]

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