{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,10]],"date-time":"2026-10-10T07:57:08Z","timestamp":1791619028799,"version":"4.3.4"},"reference-count":58,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2021,4,13]],"date-time":"2021-04-13T00:00:00Z","timestamp":1618272000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["Z1A DA000389"],"award-info":[{"award-number":["Z1A DA000389"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["Z1A DA000606"],"award-info":[{"award-number":["Z1A DA000606"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000874","name":"Brain and Behavior Research Foundation","doi-asserted-by":"publisher","award":["Young Investigator Award"],"award-info":[{"award-number":["Young Investigator Award"]}],"id":[{"id":"10.13039\/100000874","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>The dopamine D2\/D3 receptor (D2R\/D3R) agonists are used as therapeutics for Parkinson\u2019s disease (PD) and other motor disorders. Selective targeting of D3R over D2R is attractive because of D3R\u2019s restricted tissue distribution with potentially fewer side-effects and its putative neuroprotective effect. However, the high sequence homology between the D2R and D3R poses a challenge in the development of D3R selective agonists. To address the ligand selectivity, bitopic ligands were designed and synthesized previously based on a potent D3R-preferential agonist PF592,379 as the primary pharmacophore (PP). This PP was attached to various secondary pharmacophores (SPs) using chemically different linkers. Here, we characterize some of these novel bitopic ligands at both D3R and D2R using BRET-based functional assays. The bitopic ligands showed varying differences in potencies and efficacies. In addition, the chirality of the PP was key to conferring improved D3R potency, selectivity, and G protein signaling bias. In particular, compound AB04-88 exhibited significant D3R over D2R selectivity, and G protein bias at D3R. This bias was consistently observed at various time-points ranging from 8 to 46 min. Together, the structure-activity relationships derived from these functional studies reveal unique pharmacology at D3R and support further evaluation of functionally biased D3R agonists for their therapeutic potential.<\/jats:p>","DOI":"10.3390\/biom11040570","type":"journal-article","created":{"date-parts":[[2021,4,13]],"date-time":"2021-04-13T10:58:07Z","timestamp":1618311487000},"page":"570","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":21,"title":["Chirality of Novel Bitopic Agonists Determines Unique Pharmacology at the Dopamine D3 Receptor"],"prefix":"10.3390","volume":"11","author":[{"given":"Pramisha","family":"Adhikari","sequence":"first","affiliation":[{"name":"Computational Chemistry and Molecular Biophysics Section, Molecular Targets and Medications Discovery Branch, National Institute on Drug Abuse\u2014Intramural Research Program, National Institutes of Health, Baltimore, MD 21224, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1692-7199","authenticated-orcid":false,"given":"Bing","family":"Xie","sequence":"additional","affiliation":[{"name":"Computational Chemistry and Molecular Biophysics Section, Molecular Targets and Medications Discovery Branch, National Institute on Drug Abuse\u2014Intramural Research Program, National Institutes of Health, Baltimore, MD 21224, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ana","family":"Semeano","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, School of Pharmacy, Bouv\u00e9 College of Health Sciences, Northeastern University, Boston, MA 02115, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7306-0114","authenticated-orcid":false,"given":"Alessandro","family":"Bonifazi","sequence":"additional","affiliation":[{"name":"Medicinal Chemistry Section, Molecular Targets and Medications Discovery Branch, National Institute on Drug Abuse\u2014Intramural Research Program, National Institutes of Health, Baltimore, MD 21224, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francisco O.","family":"Battiti","sequence":"additional","affiliation":[{"name":"Medicinal Chemistry Section, Molecular Targets and Medications Discovery Branch, National Institute on Drug Abuse\u2014Intramural Research Program, National Institutes of Health, Baltimore, MD 21224, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amy H.","family":"Newman","sequence":"additional","affiliation":[{"name":"Medicinal Chemistry Section, Molecular Targets and Medications Discovery Branch, National Institute on Drug Abuse\u2014Intramural Research Program, National Institutes of Health, Baltimore, MD 21224, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hideaki","family":"Yano","sequence":"additional","affiliation":[{"name":"Computational Chemistry and Molecular Biophysics Section, Molecular Targets and Medications Discovery Branch, National Institute on Drug Abuse\u2014Intramural Research Program, National Institutes of Health, Baltimore, MD 21224, USA"},{"name":"Department of Pharmaceutical Sciences, School of Pharmacy, Bouv\u00e9 College of Health Sciences, Northeastern University, Boston, MA 02115, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lei","family":"Shi","sequence":"additional","affiliation":[{"name":"Computational Chemistry and Molecular Biophysics Section, Molecular Targets and Medications Discovery Branch, National Institute on Drug Abuse\u2014Intramural Research Program, National Institutes of Health, Baltimore, MD 21224, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,4,13]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"96","DOI":"10.1124\/mol.113.090563","article-title":"Discovery and characterization of a G protein-biased agonist that inhibits beta-arrestin recruitment to the D2 dopamine receptor","volume":"86","author":"Free","year":"2014","journal-title":"Mol. 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