{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,14]],"date-time":"2026-08-14T05:26:42Z","timestamp":1786685202858,"version":"build-2736575974"},"reference-count":49,"publisher":"Oxford University Press (OUP)","issue":"8","funder":[{"name":"Intramural Research Program of the National Institutes of Health","award":["ZIA DA000493"],"award-info":[{"award-number":["ZIA DA000493"]}]},{"name":"Intramural Research Program of the National Institutes of Health","award":["ZIA DA000424"],"award-info":[{"award-number":["ZIA DA000424"]}]},{"name":"Intramural Research Program of the National Institutes of Health","award":["DA058639"],"award-info":[{"award-number":["DA058639"]}]},{"name":"the Medical Research Service of the Department of Veterans Affairs"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,8,14]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Study Objectives<\/jats:title>\n                    <jats:p>We recently proposed dopamine D3 receptor (D3R) antagonists as a potential therapy for restless legs syndrome (RLS). To test this hypothesis, we evaluated two selective D3R ligands, PG01042 and PG01037, in a brain iron-deficient rat model of RLS. Their biochemical properties were also characterized and compared with pramipexole, a commonly used D2-like receptor agonist for RLS.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Periodic leg movements (PLMs) during sleep and wake and sleep fragmentation were analyzed in rats with an iron deficient diet during the postweaning period. Go protein activation and \u03b2-arrestin1 and \u03b2-arrestin2 recruitment were analyzed with BRET methodology in HEK-293T cells expressing D3R and in cells co-transfected with D3R and D1R. Molecular dynamic simulations were additionally performed to define the distinct molecular profiles of PG01042 and PG01037.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>In iron-deficient rats, PG01042 and PG01037 produced opposite behavioral effects, with PG01042 dose-dependently reducing motor symptoms and improving sleep quality, whereas PG01037 dose-dependently exacerbated motor symptoms without improving sleep. Compared with pramipexole, PG01042 behaved as a D3R partial agonist at both G protein activation and \u03b2-arrestin recruitment. In contrast, PG01037 behaved as a partial agonist for \u03b2-arrestin recruitment while exhibiting inverse agonism at G protein activation. Co-transfection with the D1R abrogated the partial efficacy of both compounds at \u03b2-arrestin recruitment. The differences in G protein activation between both ligands were attributed to subtle variations in the positioning of the chloro substituents on their 2,3-dichlorophenyl moiety.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>These findings highlight the therapeutic potential of D3R ligands with the distinct pharmacological profile of PG01042 in RLS.<\/jats:p>\n                    <jats:p>Statement of Significance The pharmacological properties of two experimental drugs that selectively target the dopamine D3 receptor (D3R) were compared in vitro and in silico and tested on the iron-deficient rat model of RLS for their ability to modify periodic leg movements (PLMs) during sleep and wake and sleep fragmentation. One of the compounds (PG01042) reduced PLMs and improved sleep, while the other (PG01037) specifically worsen PLMs. The findings suggest that drugs with the distinct pharmacological profile of PG01042 offer a promising new treatment for RLS.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1093\/sleep\/zsag134","type":"journal-article","created":{"date-parts":[[2026,5,14]],"date-time":"2026-05-14T12:08:52Z","timestamp":1778760532000},"source":"Crossref","is-referenced-by-count":1,"title":["Distinct pharmacological profile of a dopamine D3 receptor ligand with potential therapeutic effect in restless legs syndrome"],"prefix":"10.1093","volume":"49","author":[{"given":"Yuan-Yang","family":"Lai","sequence":"first","affiliation":[{"name":"Department of Psychiatry and Biobehavioral Sciences, University of California Los Angeles , Los Angeles, CA ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bradley M","family":"Keegan","sequence":"additional","affiliation":[{"name":"Computational Chemistry and Molecular Biophysics Section, National Institute on Drug Abuse, Intramural Research Program, National Institutes of Health , Baltimore, MD ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-9920-8789","authenticated-orcid":false,"given":"Marc","family":"Ciruela-Jard\u00ed","sequence":"additional","affiliation":[{"name":"Laboratory of Computational Medicine, Biostatistics Unit, Faculty of Medicine, Autonomous University of Barcelona , Barcelona ,","place":["Spain"]},{"name":"Department of Biochemistry and Molecular Biomedicine, Faculty of Biology and Institute of Biomedicine, University of Barcelona , Barcelona ,","place":["Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jian Jing","family":"Cao","sequence":"additional","affiliation":[{"name":"Medicinal Chemistry Section, National Institute on Drug Abuse, Intramural Research Program, National Institutes of Health , Baltimore, MD ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kung-Chiao","family":"Hsieh","sequence":"additional","affiliation":[{"name":"Veterans Administration Greater Los Angeles HealthCare System, Sepulveda, Los Angeles , Los Angeles, CA ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher J","family":"Earley","sequence":"additional","affiliation":[{"name":"Department of Neurology and Sleep Medicine, Johns Hopkins University School of Medicine , Baltimore, MD ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lei","family":"Shi","sequence":"additional","affiliation":[{"name":"Computational Chemistry and Molecular Biophysics Section, National Institute on Drug Abuse, Intramural Research Program, National Institutes of Health , Baltimore, MD ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Estefan\u00eda","family":"Moreno","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biomedicine, Faculty of Biology and Institute of Biomedicine, University of Barcelona , Barcelona ,","place":["Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leonardo","family":"Pardo","sequence":"additional","affiliation":[{"name":"Laboratory of Computational Medicine, Biostatistics Unit, Faculty of Medicine, Autonomous University of Barcelona , Barcelona ,","place":["Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amy H","family":"Newman","sequence":"additional","affiliation":[{"name":"Medicinal Chemistry Section, National Institute on Drug Abuse, Intramural Research Program, National Institutes of Health , Baltimore, MD ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jerome M","family":"Siegel","sequence":"additional","affiliation":[{"name":"Department of Psychiatry and Biobehavioral Sciences, University of California Los Angeles , Los Angeles, CA ,","place":["United States"]},{"name":"Veterans Administration Greater Los Angeles HealthCare System, Sepulveda, Los Angeles , Los Angeles, CA ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1747-1779","authenticated-orcid":false,"given":"Sergi","family":"Ferr\u00e9","sequence":"additional","affiliation":[{"name":"Integrative Neurobiology Section, National Institute on Drug Abuse, Intramural Research Program, National Institutes of Health , Baltimore, MD ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2026,5,15]]},"reference":[{"issue":"21","key":"2026081400265487900_ref1","doi-asserted-by":"publisher","first-page":"2103","DOI":"10.1056\/NEJMcp021288","article-title":"Clinical practice. 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