Substituted purines as high affinity histamine H3 receptor ligands

Continuing with our program to obtain new histamine H3 receptor (H3R) ligands,1-2 in this work we present the synthesis and H3R affinity studies of a series of eight purine derivatives. These compounds were designed from the isosteric replacement of the scaffold presented in our previous ligands, pyrrolo[2,3-d]pyrimidine ring, by a purine core, as well as maintaining the fragment of bipiperidine on C-4 and aromatic rings with electron withdrawing groups on N-9, since these fragments are part of the proposed pharmacophore. The in vitro screening results showed that two purine derivatives, 3d and 3h, elicited high affinities at the H3R (Ki values of 2.91 and 5.51 nM, respectively) and low toxicity in the in vitro model. In addition, through docking and, molecular dynamic studies, the binding modes were obtained with a receptor model, determining the importance of the purine ring in improving affinity.