Pyrazolo[1,5-a]pyrimidine acetamides: 4-Phenyl alkyl ether derivatives as potent ligands for the 18 kDa translocator protein (TSPO)

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Abstract

Herein, we report the synthesis of four new phenyl alkyl ether derivatives (7, 911) of the pyrazolo[1,5-a]pyrimidine acetamide class, all of which showed high binding affinity and selectivity for the TSPO and, in the case of the propyl, propargyl, and butyl ether derivatives, the ability to increase pregnenolone biosynthesis by 80–175% over baseline in rat C6 glioma cells. While these compounds fit our in silico generated pharmacophore for TSPO binding the current model does not account for the observed functional activity.

Graphical abstract

The synthesis of pyrazolo[1,5-a]pyrimidine acetamides, in vitro receptor binding and their ability to increase pregnenolone biosynthesis is reported.

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Acknowledgments

Ki determinations for targets included in the SI were generously provided by the National Institute of Mental Health′s Psychoactive Drug Screening Program, Contract #NO1MH32004 (NIMH PDSP). The NIMH PDSP is Directed by Bryan L. Roth MD, PhD at the University of North Carolina at Chapel Hill and Project Officer Jamie Driscol at NIMH, Bethesda MD, USA. For experimental details please refer to the PDSP web site http://pdsp.med.unc.edu/.

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