Potent and subtype-selective dopamine D2 receptor biased partial agonists discovered via an Ugi-based approach
| Autor: | Xerardo García-Mera, Hugo Gutiérrez-de-Terán, Aitor García-Rey, María Majellaro, Willem Jespers, Eddy Sotelo, Jhonny Azuaje, Irene Reyes-Resina, Rafael Franco, Ana Mallo-Abreu, Darío Miranda-Pastoriza, Gemma Navarro |
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| Přispěvatelé: | Universidade de Santiago de Compostela. Centro de Investigación en Química Biolóxica e Materiais Moleculares, Universidade de Santiago de Compostela. Departamento de Química Orgánica |
| Rok vydání: | 2021 |
| Předmět: |
0303 health sciences
Cell signaling Molecular model Stereochemistry Chemistry Allosteric regulation Subtype selective Ligands 01 natural sciences Partial agonist 0104 chemical sciences 010404 medicinal & biomolecular chemistry 03 medical and health sciences Dopamine receptor D2 Drug Discovery Receptors Functional selectivity Molecular Medicine Selectivity Pharmacophore Signal transduction 030304 developmental biology Agonists |
| Zdroj: | Minerva. Repositorio Institucional de la Universidad de Santiago de Compostela instname |
| Popis: | 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 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) SI |
| Databáze: | OpenAIRE |
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