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dc.contributor.authorMallo-Abreu, Ana
dc.contributor.authorReyes Resina, Irene
dc.contributor.authorAzuaje Guerrero, Jhonny Alberto
dc.contributor.authorFranco, Rafael
dc.contributor.authorGarcía Rey, Aitor
dc.contributor.authorMajellaro, María
dc.contributor.authorMiranda Pastoriza, Darío
dc.contributor.authorGarcía Mera, Xerardo Xusto
dc.contributor.authorJespers, Willem
dc.contributor.authorGutiérrez de Terán, Hugo
dc.contributor.authorNavarro, Gemma
dc.contributor.authorSotelo, Eddy
dc.date.accessioned2022-08-05T12:48:43Z
dc.date.available2022-08-05T12:48:43Z
dc.date.issued2021
dc.identifier.citationJ. Med. Chem. 2021, 64, 8710–8726. https://doi.org/10.1021/acs.jmedchem.1c00704
dc.identifier.issn0022-2623
dc.identifier.urihttp://hdl.handle.net/10347/29029
dc.description.abstractUsing 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
dc.description.sponsorshipThis 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)
dc.language.isoeng
dc.publisherACS Publications
dc.rights© 2021 American Chemical Society. This work is licenced under a Creative Commons Attribution 4.0 International licence (https://creativecommons.org/licenses/by/4.0/legalcode)
dc.rightsAtribución 4.0 Internacional
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/
dc.subjectAgonists
dc.subjectCell signaling
dc.subjectLigands
dc.subjectReceptors
dc.subjectSelectivity
dc.titlePotent and subtype-selective dopamine D2 receptor biased partial agonists discovered via an Ugi-based approach
dc.typeinfo:eu-repo/semantics/article
dc.identifier.DOI10.1021/acs.jmedchem.1c00704
dc.relation.publisherversionhttps://doi.org/10.1021/acs.jmedchem.1c00704
dc.type.versioninfo:eu-repo/semantics/publishedVersion
dc.rights.accessrightsinfo:eu-repo/semantics/openAccess
dc.contributor.affiliationUniversidade de Santiago de Compostela. Centro de Investigación en Química Biolóxica e Materiais Moleculares
dc.contributor.affiliationUniversidade de Santiago de Compostela. Departamento de Química Orgánica
dc.description.peerreviewedSI


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© 2021 American Chemical Society. This work is licenced under a Creative Commons Attribution 4.0 International licence (https://creativecommons.org/licenses/by/4.0/legalcode)
Except where otherwise noted, this item's license is described as  © 2021 American Chemical Society. This work is licenced under a Creative Commons Attribution 4.0 International licence (https://creativecommons.org/licenses/by/4.0/legalcode)





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