Synthesis of novel 7-imino-2-thioxo-3,7-dihydro-2H-thiazolo [4,5-d] pyrimidine derivatives as adenosine A2A receptor antagonists.
Novel bicyclic thiazolopyrimidine compounds (15-26) were synthesized to develop adenosine A(2A) receptor (A(2A)R) antagonist for the treatment of Parkinson's disease (PD). The binding affinity of the compounds (15-26) with A(2A)R was evaluated using radioligand binding assay on isolated membranes from stably transfected HEK293 cells. Selectivity of the compounds towards A(2A)R was assessed by comparing their binding affinities with A(1) receptors (A(1)R). cAMP concentrations were measured from HEK293 cells treated with compounds (15-26) as compared to NECA (A(2A)R agonist). The compound (16) possessed strongest A(2A)R binding affinity (K(i) value=0.0038 nM) and selectivity (737-fold) versus A(1)R. Decrease in A(2A)R-coupled release of endogenous cAMP from HEK293 cells treated with compounds (15-26) is evocative of their potential as A(2A)R antagonist.
Luthra
Pratibha Mehta
PM
Medicinal Chemistry Division, Dr BR Ambedkar Center for Biomedical Research, University of Delhi, Delhi 110 007, India. pmluthra@acbr.du.ac.in
Mishra
Chandra Bhushan
CB
Jha
Pawan Kumar
PK
Barodia
Sandeep Kumar
SK
D058917:Adenosine A2 Receptor Antagonists; D002460:Cell Line; D006801:Humans; D011485:Protein Binding; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000378:metabolism* / Q000494:pharmacology; D043705:Receptor, Adenosine A2A / Q000378:metabolism*; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000138:chemical synthesis* / Q000378:metabolism* / Q000494:pharmacology
D058917:Adenosine A2 Receptor Antagonists; D011743:Pyrimidines; D043705:Receptor, Adenosine A2A; D013844:Thiazoles