Show simple item record

dc.contributor.authorChun, Lani S.
dc.contributor.authorVekariya, Rakesh H.
dc.contributor.authorFree, R. Benjamin
dc.contributor.authorLi, Yun
dc.contributor.authorLin, Da-Ting
dc.contributor.authorSu, Ping
dc.contributor.authorLiu, Fang
dc.contributor.authorNamkung, Yoon
dc.contributor.authorLaporte, Stephane A.
dc.contributor.authorMoritz, Amy E.
dc.contributor.authorAubé, Jeffrey
dc.contributor.authorFrankowski, Kevin J.
dc.contributor.authorSibley, David R.
dc.date.accessioned2018-04-26T17:23:08Z
dc.date.available2018-04-26T17:23:08Z
dc.date.issued2018-02-21
dc.identifier.citationChun, L. S., Vekariya, R. H., Free, R. B., Li, Y., Lin, D.-T., Su, P., … Sibley, D. R. (2018). Structure-Activity Investigation of a G Protein-Biased Agonist Reveals Molecular Determinants for Biased Signaling of the D2 Dopamine Receptor. Frontiers in Synaptic Neuroscience, 10, 2. http://doi.org/10.3389/fnsyn.2018.00002en_US
dc.identifier.urihttp://hdl.handle.net/1808/26371
dc.description.abstractThe dopamine D2 receptor (D2R) is known to elicit effects through activating two major signaling pathways mediated by either G proteins (Gi/o) or β-arrestins. However, the specific role of each pathway in physiological or therapeutic activities is not known with certainty. One approach to the dissection of these pathways is through the use of drugs that can selectively modulate one pathway vs. the other through a mechanism known as functional selectivity or biased signaling. Our laboratory has previously described a G protein signaling-biased agonist, MLS1547, for the D2R using a variety of in vitro functional assays. To further evaluate the biased signaling activity of this compound, we investigated its ability to promote D2R internalization, a process known to be mediated by β-arrestin. Using multiple cellular systems and techniques, we found that MLS1547 promotes little D2R internalization, which is consistent with its inability to recruit β-arrestin. Importantly, we validated these results in primary striatal neurons where the D2R is most highly expressed suggesting that MLS1547 will exhibit biased signaling activity in vivo. In an effort to optimize and further explore structure-activity relationships (SAR) for this scaffold, we conducted an iterative chemistry campaign to synthesize and characterize novel analogs of MLS1547. The resulting analysis confirmed previously described SAR requirements for G protein-biased agonist activity and, importantly, elucidated new structural features that are critical for agonist efficacy and signaling bias of the MLS1547 scaffold. One of the most important determinants for G protein-biased signaling is the interaction of a hydrophobic moiety of the compound with a defined pocket formed by residues within transmembrane five and extracellular loop two of the D2R. These results shed new light on the mechanism of biased signaling of the D2R and may lead to improved functionally-selective molecules.en_US
dc.publisherFrontiers Mediaen_US
dc.rightsCopyright © 2018 Chun, Vekariya, Free, Li, Lin, Su, Liu, Namkung, Laporte, Moritz, Aubé, Frankowski and Sibley. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.en_US
dc.subjectD2 dopamine receptoren_US
dc.subjectFunctional selectivityen_US
dc.subjectBiased signalingen_US
dc.subjectStructure-activity relationshipen_US
dc.subjectMLS1547en_US
dc.subjectQuinolineen_US
dc.titleStructure-Activity Investigation of a G Protein-Biased Agonist Reveals Molecular Determinants for Biased Signaling of the D2 Dopamine Receptoren_US
dc.typeArticleen_US
kusw.kudepartmentMedicinal Chemistryen_US
dc.identifier.doi10.3389/fnsyn.2018.00002en_US
dc.identifier.orcidhttps://orcid.org/0000-0003-1049-5767 https://orcid.org/0000-0001-8292-9793
kusw.oaversionScholarly/refereed, publisher versionen_US
kusw.oapolicyThis item meets KU Open Access policy criteria.en_US
dc.rights.accessrightsopenAccessen_US


Files in this item

Thumbnail

This item appears in the following Collection(s)

Show simple item record