期刊
PHARMACEUTICALS
卷 15, 期 5, 页码 -出版社
MDPI
DOI: 10.3390/ph15050573
关键词
histamine H-3 receptor; H3R ligands; purines; in silico studies; ADME prediction
资金
- FONDECYT Research Grant [1180292]
- DFG [GRK2158]
In this study, a series of new purine derivatives were synthesized and screened for their affinity to H3R. Two compounds showed high affinity to H3R and were more potent than the reference drug. Molecular modeling studies revealed the importance of the purine ring in enhancing affinity through hydrogen bonding. These findings suggest that these molecules have promising potential as H3R ligands.
Continuing with our program to obtain new histamine H-3 receptor (H3R) ligands, in this work we present the synthesis, H3R affinity and in silico studies of a series of eight new synthetically accessible purine derivatives. These compounds are designed from the isosteric replacement of the scaffold presented in our previous ligand, pyrrolo[2,3-d]pyrimidine ring, by a purine core. This design also considers maintaining the fragment of bipiperidine at C-4 and aromatic rings with electron-withdrawing groups at N-9, as these fragments are part of the proposed pharmacophore. The in vitro screening results show that two purine derivatives, 3d and 3h, elicit high affinities to the H3R (Ki values of 2.91 and 5.51 nM, respectively). Both compounds are more potent than the reference drug pitolisant (Ki 6.09 nM) and show low toxicity with in vitro models (IC50 > 30 mu M on HEK-293, SH-SY5Y and HepG2 cell lines). Subsequently, binding modes of these ligands are obtained using a model of H3R by docking and molecular dynamics studies, thus determining the importance of the purine ring in enhancing affinity due to the hydrogen bonding of Tyr374 to the N-7 of this heterocycle. Finally, in silico ADME properties are predicted, which indicate a promising future for these molecules in terms of their physical-chemical properties, absorption, oral bioavailability and penetration in the CNS.
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