1-phenylpyrazolo[3,4-d]pyrimidines; Structure-activity relationships for C6 substituents at A(1) and A(2A) adenosine receptors

Substitution of 1-phenylpyrazolo[3,4-d]pyrimidines at C6 with N-alkyl-2-thi opropionamide groups has resulted in a series of 18 compounds which have be en evaluated for binding at A(1) and A(2A) adenosine receptors. introductio n of an N-ethyl group gave increased affinity at both A(1) and A(2A) recept ors for the amino compound 7b compared to the primary amide 7a. An addition al hydrophobic pocket exists for substituents on the amide. This pocket all ows an N-ethyl group for increased affinity at both A(1) and A(2A) receptor s, allows larger alkyl groups at A(2A) receptors but not at A(1) receptors and there is an H-bond interaction requiring one H-bond donor. Molecular mo deling studies have also enabled a proposal of the amino acid residues invo lved in ligand binding at both the A(1) and A(2A) receptors. (C) 2000 Elsev ier Science Ltd. All rights reserved.