RT Journal Article
T1 Potent and subtype-selective dopamine D2 receptor biased partial agonists discovered via an Ugi-based approach
A1 Mallo-Abreu, Ana
A1 Reyes Resina, Irene
A1 Azuaje Guerrero, Jhonny Alberto
A1 Franco, Rafael
A1 García Rey, Aitor
A1 Majellaro, María
A1 Miranda Pastoriza, Darío
A1 García Mera, Xerardo
A1 Jespers, Willem
A1 Gutiérrez de Terán, Hugo
A1 Navarro, Gemma
A1 Sotelo Pérez, Eddy
K1 Agonists
K1 Cell signaling
K1 Ligands
K1 Receptors
K1 Selectivity
AB Using a previously unexplored, efficient, and versatile multicomponent method, we herein report the rapid generation of novel potent and subtype-selective DRD2 biased partial agonists. This strategy exemplifies the search for diverse and previously unexplored moieties for the secondary/allosteric pharmacophore of the common phenyl-piperazine scaffold. The pharmacological characterization of the new compound series led to the identification of several ligands with excellent DRD2 affinity and subtype selectivity and remarkable functional selectivity for either the cAMP (22a and 24d) or the β-arrestin (27a and 29c) signaling pathways. These results were further interpreted on the basis of molecular models of these ligands in complex with the recent DRD2 crystal structures, highlighting the critical role of the secondary/allosteric pharmacophore in modulating the functional selectivity profile
PB ACS Publications
SN 0022-2623
YR 2021
FD 2021
LK http://hdl.handle.net/10347/29029
UL http://hdl.handle.net/10347/29029
LA eng
NO J. Med. Chem. 2021, 64, 8710–8726. https://doi.org/10.1021/acs.jmedchem.1c00704
NO This work was financially supported by the Consellería de Cultura, Educación e Ordenación Universitaria of the Galician Government: (grant: ED431B 2020/43), Centro Singular de Investigación de Galicia accreditation 2019-2022 (ED431G 2019/03), the Spanish Ministerio de Economía y Competitividad (SAF2017-84117-R), the European Regional Development Fund (ERDF) and the Swedish Research Council. Additional support from the Swedish strategic research program eSSENCE and Deputación da Coruña (grant: 2019000011466) are acknowledged. The computations were performed on resources provided by the Swedish National Infrastructure for Computing (SNIC). This research program was developed within the framework of the European COST action ERNEST (CA 18133)
DS Minerva
RD 24 abr 2026