{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,11]],"date-time":"2026-02-11T13:03:51Z","timestamp":1770815031801,"version":"3.50.1"},"reference-count":67,"publisher":"Wiley","issue":"13","license":[{"start":{"date-parts":[[2025,3,27]],"date-time":"2025-03-27T00:00:00Z","timestamp":1743033600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003554","name":"Lundbeckfonden","doi-asserted-by":"publisher","award":["R383\u20102022\u2010306"],"award-info":[{"award-number":["R383\u20102022\u2010306"]}],"id":[{"id":"10.13039\/501100003554","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["bpspubs.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["British J Pharmacology"],"published-print":{"date-parts":[[2025,7]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background and Purpose<\/jats:title><jats:p>Preclinical studies suggest that highly selective dopamine D<jats:sub>3<\/jats:sub> receptor (D<jats:sub>3<\/jats:sub>R) antagonists or partial agonists hold promise for treating substance use disorders. However, their limited effectiveness in reducing cocaine self\u2010administration is a major drawback. This study investigated whether cariprazine (D<jats:sub>3<\/jats:sub> receptor\u2010preferring partial agonist) and its analogues ESG\u20101\u201060 and ESG\u20101\u201061 have enhanced efficacy in reducing cocaine\u2010taking and cocaine\u2010seeking behaviour.<\/jats:p><\/jats:sec><jats:sec><jats:title>Experimental Approach<\/jats:title><jats:p>In vitro BRET experiments were used to characterize the functional efficacies of cariprazine and its analogues. Intravenous cocaine self\u2010administration and reinstatement models were used to evaluate efficacy in reducing cocaine\u2010taking and cocaine\u2010seeking behaviour. Optical intracranial self\u2010stimulation (oICSS) procedures assessed effects on dopamine\u2010dependent behaviour. Open\u2010field locomotion, oral sucrose self\u2010administration and conditioned place\u2010preference were used to evaluate potential unwanted side effects.<\/jats:p><\/jats:sec><jats:sec><jats:title>Key Results<\/jats:title><jats:p>BRET functional assays indicated that cariprazine and ESG\u20101\u201060 are D<jats:sub>3<\/jats:sub> receptor\u2010preferring partial agonists, while ESG\u20101\u201061 is a D<jats:sub>3<\/jats:sub> receptor\u2010preferring antagonist\/inverse agonist. All three compounds inhibited cocaine self\u2010administration under both fixed\u2010ratio and progressive\u2010ratio reinforcement schedules and reduced cocaine\u2010induced reinstatement of drug\u2010seeking behaviour in both male and female rats. The compounds did not alter locomotor behaviour but suppressed sucrose intake and dopamine\u2010dependent oICSS. Cariprazine and ESG\u20101\u201061 produced significant place aversion, while ESG\u20101\u201060 did not. Chronic administration of ESG\u20101\u201060 inhibited cocaine self\u2010administration.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions and Implications<\/jats:title><jats:p>Novel D<jats:sub>3<\/jats:sub> receptor\u2010preferring compounds ESG\u20101\u201060 and ESG\u20101\u201061 were highly effective in reducing cocaine\u2010taking and cocaine\u2010seeking, under various reinforcement conditions. ESG\u20101\u201060 warrants further investigation as a new pharmacotherapy for treating cocaine use disorder as it is effective in these models and lacks unwanted behavioural effects.<\/jats:p><\/jats:sec>","DOI":"10.1111\/bph.70021","type":"journal-article","created":{"date-parts":[[2025,3,30]],"date-time":"2025-03-30T12:42:48Z","timestamp":1743338568000},"page":"2997-3016","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["ESG\u20101\u201060 and ESG\u20101\u201061: Novel dopamine D<sub>3<\/sub> receptor\u2010preferring partial agonists\/antagonists that inhibit cocaine taking and seeking in rodents"],"prefix":"10.1111","volume":"182","author":[{"given":"Omar","family":"Soler\u2010Cede\u00f1o","sequence":"first","affiliation":[{"name":"Addiction Biology Unit, Molecular Targets and Medications Discovery Branch National Institute on Drug Abuse  Baltimore Maryland USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bradley M.","family":"Keegan","sequence":"additional","affiliation":[{"name":"Medicinal Chemistry Section, Molecular Targets and Medications Discovery Branch National Institute on Drug Abuse  Baltimore Maryland USA"},{"name":"Computational Chemistry and Molecular Biophysics Section, Molecular Targets and Medications Discovery Branch National Institute on Drug Abuse  Baltimore Maryland USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hannah","family":"Alton","sequence":"additional","affiliation":[{"name":"Addiction Biology Unit, Molecular Targets and Medications Discovery Branch National Institute on Drug Abuse  Baltimore Maryland USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Guo\u2010Hua","family":"Bi","sequence":"additional","affiliation":[{"name":"Addiction Biology Unit, Molecular Targets and Medications Discovery Branch National Institute on Drug Abuse  Baltimore Maryland USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Emily","family":"Linz","sequence":"additional","affiliation":[{"name":"Addiction Biology Unit, Molecular Targets and Medications Discovery Branch National Institute on Drug Abuse  Baltimore Maryland USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Caleb D.","family":"Vogt","sequence":"additional","affiliation":[{"name":"Medicinal Chemistry Section, Molecular Targets and Medications Discovery Branch National Institute on Drug Abuse  Baltimore Maryland USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Emma S.","family":"Gogarnoiu","sequence":"additional","affiliation":[{"name":"Medicinal Chemistry Section, Molecular Targets and Medications Discovery Branch National Institute on Drug Abuse  Baltimore Maryland USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"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  Baltimore Maryland USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Amy Hauck","family":"Newman","sequence":"additional","affiliation":[{"name":"Medicinal Chemistry Section, Molecular Targets and Medications Discovery Branch National Institute on Drug Abuse  Baltimore Maryland USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6482-8104","authenticated-orcid":false,"given":"Zheng\u2010Xiong","family":"Xi","sequence":"additional","affiliation":[{"name":"Addiction Biology Unit, Molecular Targets and Medications Discovery Branch National Institute on Drug Abuse  Baltimore Maryland USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2025,3,27]]},"reference":[{"key":"e_1_2_12_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bmcl.2012.03.104"},{"key":"e_1_2_12_3_1","volume-title":"Provisional drug overdose death counts","author":"Ahmad F. B.","year":"2023"},{"key":"e_1_2_12_4_1","doi-asserted-by":"publisher","DOI":"10.1111\/bph.16177"},{"key":"e_1_2_12_5_1","doi-asserted-by":"publisher","DOI":"10.1111\/bph.16182"},{"key":"e_1_2_12_6_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1600-0447.2005.00539.x"},{"key":"e_1_2_12_7_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jmedchem.6b01875"},{"key":"e_1_2_12_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2010.11.022"},{"key":"e_1_2_12_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.pbb.2010.04.001"},{"key":"e_1_2_12_10_1","doi-asserted-by":"publisher","DOI":"10.1111\/bdi.12794"},{"key":"e_1_2_12_11_1","doi-asserted-by":"publisher","DOI":"10.1111\/bph.15868"},{"key":"e_1_2_12_12_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.20-23-08677.2000"},{"key":"e_1_2_12_13_1","doi-asserted-by":"publisher","DOI":"10.2147\/NDT.S367922"},{"key":"e_1_2_12_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jad.2019.11.098"},{"key":"e_1_2_12_15_1","doi-asserted-by":"publisher","DOI":"10.1111\/bdi.12852"},{"key":"e_1_2_12_16_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jmedchem.9b00864"},{"key":"e_1_2_12_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.drugalcdep.2005.05.011"},{"key":"e_1_2_12_18_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.0988-20.2020"},{"key":"e_1_2_12_19_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neubiorev.2020.04.024"},{"key":"e_1_2_12_20_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jmedchem.2c01624"},{"key":"e_1_2_12_21_1","doi-asserted-by":"publisher","DOI":"10.1007\/BF01271201"},{"key":"e_1_2_12_22_1","doi-asserted-by":"publisher","DOI":"10.1124\/jpet.106.107920"},{"key":"e_1_2_12_23_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.1493-22.2022"},{"key":"e_1_2_12_24_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41401-018-0059-x"},{"key":"e_1_2_12_25_1","doi-asserted-by":"publisher","DOI":"10.3390\/molecules28135270"},{"key":"e_1_2_12_26_1","doi-asserted-by":"publisher","DOI":"10.1111\/adb.13005"},{"key":"e_1_2_12_27_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuropharm.2019.04.015"},{"key":"e_1_2_12_28_1","doi-asserted-by":"publisher","DOI":"10.1111\/bph.15244"},{"key":"e_1_2_12_29_1","doi-asserted-by":"publisher","DOI":"10.1124\/jpet.119.259390"},{"key":"e_1_2_12_30_1","doi-asserted-by":"publisher","DOI":"10.1002\/med.21923"},{"key":"e_1_2_12_31_1","doi-asserted-by":"publisher","DOI":"10.1016\/B978-0-12-420118-7.00007-X"},{"key":"e_1_2_12_32_1","doi-asserted-by":"publisher","DOI":"10.4088\/JCP.13r08525"},{"key":"e_1_2_12_33_1","doi-asserted-by":"publisher","DOI":"10.1124\/jpet.109.160432"},{"key":"e_1_2_12_34_1","doi-asserted-by":"publisher","DOI":"10.3390\/biom11010104"},{"key":"e_1_2_12_35_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neubiorev.2021.06.038"},{"key":"e_1_2_12_36_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.mcn.2023.103859"},{"key":"e_1_2_12_37_1","doi-asserted-by":"publisher","DOI":"10.1007\/s12325-021-01797-5"},{"key":"e_1_2_12_38_1","doi-asserted-by":"publisher","DOI":"10.1111\/bph.15178"},{"key":"e_1_2_12_39_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0022-3565(24)37395-1"},{"key":"e_1_2_12_40_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.clinthera.2023.10.015"},{"key":"e_1_2_12_41_1","doi-asserted-by":"publisher","DOI":"10.1111\/jnc.13732"},{"key":"e_1_2_12_42_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jmedchem.6b01148"},{"key":"e_1_2_12_43_1","doi-asserted-by":"publisher","DOI":"10.1152\/physrev.1998.78.1.189"},{"key":"e_1_2_12_44_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuroscience.2016.05.017"},{"key":"e_1_2_12_45_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejphar.2015.02.025"},{"key":"e_1_2_12_46_1","doi-asserted-by":"publisher","DOI":"10.1097\/YCO.0000000000000510"},{"key":"e_1_2_12_47_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-pharmtox-030220-124205"},{"key":"e_1_2_12_48_1","doi-asserted-by":"publisher","DOI":"10.1007\/7854_2022_347"},{"key":"e_1_2_12_49_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pbio.3000410"},{"key":"e_1_2_12_50_1","doi-asserted-by":"publisher","DOI":"10.3389\/fpsyt.2021.769623"},{"key":"e_1_2_12_51_1","doi-asserted-by":"publisher","DOI":"10.1136\/bmjno-2020-000057"},{"key":"e_1_2_12_52_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ypmed.2023.107625"},{"key":"e_1_2_12_53_1","doi-asserted-by":"publisher","DOI":"10.1080\/10550887.2021.1945398"},{"key":"e_1_2_12_54_1","doi-asserted-by":"publisher","DOI":"10.3389\/fpsyt.2021.727666"},{"key":"e_1_2_12_55_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00213-012-2906-7"},{"key":"e_1_2_12_56_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.yfrne.2023.101085"},{"key":"e_1_2_12_57_1","doi-asserted-by":"publisher","DOI":"10.1021\/acsptsci.4c00119"},{"key":"e_1_2_12_58_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00213-002-1224-x"},{"key":"e_1_2_12_59_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41380-023-02203-y"},{"key":"e_1_2_12_60_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41386-024-01861-y"},{"key":"e_1_2_12_61_1","doi-asserted-by":"publisher","DOI":"10.1111\/acps.13266"},{"key":"e_1_2_12_62_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0022-3565(24)39024-X"},{"key":"e_1_2_12_63_1","doi-asserted-by":"publisher","DOI":"10.2165\/00023210-200216010-00003"},{"key":"e_1_2_12_64_1","doi-asserted-by":"publisher","DOI":"10.3390\/genes13050892"},{"key":"e_1_2_12_65_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.biopsych.2024.05.020"},{"key":"e_1_2_12_66_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.npp.1301552"},{"key":"e_1_2_12_67_1","doi-asserted-by":"publisher","DOI":"10.1016\/0304-3940(94)90510-X"},{"key":"e_1_2_12_68_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41386-018-0284-5"}],"container-title":["British Journal of Pharmacology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/bpspubs.onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/bph.70021","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,9,12]],"date-time":"2025-09-12T08:53:42Z","timestamp":1757667222000},"score":1,"resource":{"primary":{"URL":"https:\/\/bpspubs.onlinelibrary.wiley.com\/doi\/10.1111\/bph.70021"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,3,27]]},"references-count":67,"journal-issue":{"issue":"13","published-print":{"date-parts":[[2025,7]]}},"alternative-id":["10.1111\/bph.70021"],"URL":"https:\/\/doi.org\/10.1111\/bph.70021","archive":["Portico"],"relation":{},"ISSN":["0007-1188","1476-5381"],"issn-type":[{"value":"0007-1188","type":"print"},{"value":"1476-5381","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,3,27]]},"assertion":[{"value":"2024-09-30","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-01-27","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-03-27","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}