Repositorio
Institucional

Espinosa-Bustos, Christian

Leitzbach, Luisa

Anazco, Tito

Silva, Maria J.

del Campo, Andrea

Castro-Alvarez, Alejandro

Stark, Holger

Salas, Cristian O.

Substituted Purines as High-Affinity Histamine H-3 Receptor Ligands

MDPI

PHARMACEUTICALS

en

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.

artículo original

C.E.-B. gratefully acknowledges the financial support from FONDECYT Research Grant No. 1180292. The partial support of DFG GRK2158 is greatly acknowledged (by H.S.).

C.E.-B. agradece el apoyo financiero de la Beca de Investigación FONDECYT No. 1180292. Se agradece enormemente el apoyo parcial de DFG GRK2158 (por parte de H.S.).

10.3390/ph15050573

PDF

histamine H-3 receptor

H3R ligands

purines

in silico studies

ADME prediction

PROTEIN

DERIVATIVES

INHIBITION

GENERATION

DESIGN

POTENT

GPCRDB

Química Medicinal

Farmacología y farmacia

receptor de histamina H-3

ligandos H3R

purinas

estudios in silico

predicción ADME

PROTEÍNAS

DERIVADOS

INHIBICIÓN

GENERACIÓN

DISEÑO

POTENTE

GPCRDB

Substituted Purines as High-Affinity Histamine H-3 Receptor Ligands

artículo original

version publicada

CC BY 4.0

CC BY 4.0

acceso abierto

acceso abierto

ANID-FONDECYT 1180292

DFG GRK2158

ANID FONDECYT 1180292

WOS:000801251200001