Pyrazolo[1,5-a]pyrimidine acetamides: 4-Phenyl alkyl ether derivatives as potent ligands for the 18 kDa translocator protein (TSPO).
Herein, we report the synthesis of four new phenyl alkyl ether derivatives (7, 9-11) 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.
Reynolds
Aaron
A
School of Chemistry, University of Sydney, Sydney, NSW 2006, Australia.
Hanani
Raphy
R
Hibbs
David
D
Damont
Annelaure
A
Da Pozzo
Eleonora
E
Selleri
Silvia
S
Dollé
Frédéric
F
Martini
Claudia
C
Kassiou
Michael
M
D000081:Acetamides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D000818:Animals; D002352:Carrier Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D045744:Cell Line, Tumor; D004987:Ethers / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D008024:Ligands; D011284:Pregnenolone / Q000096:biosynthesis; D011485:Protein Binding; D011720:Pyrazoles / Q000737:chemistry*; D011725:Pyridines / Q000737:chemistry*; D051381:Rats; D011963:Receptors, GABA-A / Q000378:metabolism
D000081:Acetamides; D002352:Carrier Proteins; D004987:Ethers; D008024:Ligands; D011720:Pyrazoles; D011725:Pyridines; D011963:Receptors, GABA-A; C118531:pyrazolopyridine; C069997:Tspo protein, rat; D011284:Pregnenolone