Cargando…
Novel and Potent Dopamine D(2) Receptor Go-Protein Biased Agonists
[Image: see text] The discovery of functionally biased and physiologically beneficial ligands directed toward G-protein coupled receptors (GPCRs) has provided the impetus to design dopamine D(2) receptor (D(2)R) targeted molecules that may be therapeutically advantageous for the treatment of certain...
Autores principales: | , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American
Chemical Society
2019
|
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6371206/ https://www.ncbi.nlm.nih.gov/pubmed/30775693 http://dx.doi.org/10.1021/acsptsci.8b00060 |
_version_ | 1783394529448034304 |
---|---|
author | Bonifazi, Alessandro Yano, Hideaki Guerrero, Adrian M. Kumar, Vivek Hoffman, Alexander F. Lupica, Carl R. Shi, Lei Newman, Amy Hauck |
author_facet | Bonifazi, Alessandro Yano, Hideaki Guerrero, Adrian M. Kumar, Vivek Hoffman, Alexander F. Lupica, Carl R. Shi, Lei Newman, Amy Hauck |
author_sort | Bonifazi, Alessandro |
collection | PubMed |
description | [Image: see text] The discovery of functionally biased and physiologically beneficial ligands directed toward G-protein coupled receptors (GPCRs) has provided the impetus to design dopamine D(2) receptor (D(2)R) targeted molecules that may be therapeutically advantageous for the treatment of certain neuropsychiatric or basal ganglia related disorders. Here we describe the synthesis of a novel series of D(2)R agonists linking the D(2)R unbiased agonist sumanirole with privileged secondary molecular fragments. The resulting ligands demonstrate improved D(2)R affinity and selectivity over sumanirole. Extensive in vitro functional studies and bias factor analysis led to the identification of a novel class of highly potent Go-protein biased full D(2)R agonists with more than 10-fold and 1000-fold bias selectivity toward activation of specific G-protein subtypes and β-arrestin, respectively. Intracellular electrophysiological recordings from midbrain dopamine neurons demonstrated that Go-protein selective agonists can elicit prolonged ligand-induced GIRK activity via D(2)Rs, which may be beneficial in the treatment of dyskinesias associated with dopamine system dysfunction. |
format | Online Article Text |
id | pubmed-6371206 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | American
Chemical Society |
record_format | MEDLINE/PubMed |
spelling | pubmed-63712062019-02-14 Novel and Potent Dopamine D(2) Receptor Go-Protein Biased Agonists Bonifazi, Alessandro Yano, Hideaki Guerrero, Adrian M. Kumar, Vivek Hoffman, Alexander F. Lupica, Carl R. Shi, Lei Newman, Amy Hauck ACS Pharmacol Transl Sci [Image: see text] The discovery of functionally biased and physiologically beneficial ligands directed toward G-protein coupled receptors (GPCRs) has provided the impetus to design dopamine D(2) receptor (D(2)R) targeted molecules that may be therapeutically advantageous for the treatment of certain neuropsychiatric or basal ganglia related disorders. Here we describe the synthesis of a novel series of D(2)R agonists linking the D(2)R unbiased agonist sumanirole with privileged secondary molecular fragments. The resulting ligands demonstrate improved D(2)R affinity and selectivity over sumanirole. Extensive in vitro functional studies and bias factor analysis led to the identification of a novel class of highly potent Go-protein biased full D(2)R agonists with more than 10-fold and 1000-fold bias selectivity toward activation of specific G-protein subtypes and β-arrestin, respectively. Intracellular electrophysiological recordings from midbrain dopamine neurons demonstrated that Go-protein selective agonists can elicit prolonged ligand-induced GIRK activity via D(2)Rs, which may be beneficial in the treatment of dyskinesias associated with dopamine system dysfunction. American Chemical Society 2019-01-14 /pmc/articles/PMC6371206/ /pubmed/30775693 http://dx.doi.org/10.1021/acsptsci.8b00060 Text en Copyright © 2019 American Chemical Society This is an open access article published under an ACS AuthorChoice License (http://pubs.acs.org/page/policy/authorchoice_termsofuse.html) , which permits copying and redistribution of the article or any adaptations for non-commercial purposes. |
spellingShingle | Bonifazi, Alessandro Yano, Hideaki Guerrero, Adrian M. Kumar, Vivek Hoffman, Alexander F. Lupica, Carl R. Shi, Lei Newman, Amy Hauck Novel and Potent Dopamine D(2) Receptor Go-Protein Biased Agonists |
title | Novel and Potent Dopamine D(2) Receptor Go-Protein
Biased Agonists |
title_full | Novel and Potent Dopamine D(2) Receptor Go-Protein
Biased Agonists |
title_fullStr | Novel and Potent Dopamine D(2) Receptor Go-Protein
Biased Agonists |
title_full_unstemmed | Novel and Potent Dopamine D(2) Receptor Go-Protein
Biased Agonists |
title_short | Novel and Potent Dopamine D(2) Receptor Go-Protein
Biased Agonists |
title_sort | novel and potent dopamine d(2) receptor go-protein
biased agonists |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6371206/ https://www.ncbi.nlm.nih.gov/pubmed/30775693 http://dx.doi.org/10.1021/acsptsci.8b00060 |
work_keys_str_mv | AT bonifazialessandro novelandpotentdopamined2receptorgoproteinbiasedagonists AT yanohideaki novelandpotentdopamined2receptorgoproteinbiasedagonists AT guerreroadrianm novelandpotentdopamined2receptorgoproteinbiasedagonists AT kumarvivek novelandpotentdopamined2receptorgoproteinbiasedagonists AT hoffmanalexanderf novelandpotentdopamined2receptorgoproteinbiasedagonists AT lupicacarlr novelandpotentdopamined2receptorgoproteinbiasedagonists AT shilei novelandpotentdopamined2receptorgoproteinbiasedagonists AT newmanamyhauck novelandpotentdopamined2receptorgoproteinbiasedagonists |