ESG‐1‐60 and ESG‐1‐61: Novel dopamine D3 receptor‐preferring partial agonists/antagonists that inhibit cocaine taking and seeking in rodents
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2025
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| author | Omar Soler‐Cedeño Bradley M. Keegan Hannah Alton Guo‐Hua Bi Emily Linz Caleb D. Vogt Emma S. Gogarnoiu Lei Shi Amy Hauck Newman Zheng‐Xiong Xi |
| author_facet | Omar Soler‐Cedeño Bradley M. Keegan Hannah Alton Guo‐Hua Bi Emily Linz Caleb D. Vogt Emma S. Gogarnoiu Lei Shi Amy Hauck Newman Zheng‐Xiong Xi Omar Soler‐Cedeño Bradley M. Keegan Hannah Alton Guo‐Hua Bi Emily Linz Caleb D. Vogt Emma S. Gogarnoiu Lei Shi Amy Hauck Newman Zheng‐Xiong Xi |
| collection | Wiley Open Access |
| contents | ESG‐1‐60 and ESG‐1‐61: Novel dopamine D3 receptor‐preferring partial agonists/antagonists that inhibit cocaine taking and seeking in rodents Omar Soler‐Cedeño Bradley M. Keegan Hannah Alton Guo‐Hua Bi Emily Linz Caleb D. Vogt Emma S. Gogarnoiu Lei Shi Amy Hauck Newman Zheng‐Xiong Xi British Journal of Pharmacology AbstractBackground and PurposePreclinical studies suggest that highly selective dopamine D3 receptor (D3R) antagonists or partial agonists hold promise for treating substance use disorders. However, their limited effectiveness in reducing cocaine self‐administration is a major drawback. This study investigated whether cariprazine (D3 receptor‐preferring partial agonist) and its analogues ESG‐1‐60 and ESG‐1‐61 have enhanced efficacy in reducing cocaine‐taking and cocaine‐seeking behaviour.Experimental ApproachIn vitro BRET experiments were used to characterize the functional efficacies of cariprazine and its analogues. Intravenous cocaine self‐administration and reinstatement models were used to evaluate efficacy in reducing cocaine‐taking and cocaine‐seeking behaviour. Optical intracranial self‐stimulation (oICSS) procedures assessed effects on dopamine‐dependent behaviour. Open‐field locomotion, oral sucrose self‐administration and conditioned place‐preference were used to evaluate potential unwanted side effects.Key ResultsBRET functional assays indicated that cariprazine and ESG‐1‐60 are D3 receptor‐preferring partial agonists, while ESG‐1‐61 is a D3 receptor‐preferring antagonist/inverse agonist. All three compounds inhibited cocaine self‐administration under both fixed‐ratio and progressive‐ratio reinforcement schedules and reduced cocaine‐induced reinstatement of drug‐seeking behaviour in both male and female rats. The compounds did not alter locomotor behaviour but suppressed sucrose intake and dopamine‐dependent oICSS. Cariprazine and ESG‐1‐61 produced significant place aversion, while ESG‐1‐60 did not. Chronic administration of ESG‐1‐60 inhibited cocaine self‐administration.Conclusions and ImplicationsNovel D3 receptor‐preferring compounds ESG‐1‐60 and ESG‐1‐61 were highly effective in reducing cocaine‐taking and cocaine‐seeking, under various reinforcement conditions. ESG‐1‐60 warrants further investigation as a new pharmacotherapy for treating cocaine use disorder as it is effective in these models and lacks unwanted behavioural effects. 10.1111/bph.70021 http://creativecommons.org/licenses/by-nc/4.0/ |
| doi_str_mv | 10.1111/bph.70021 |
| format | Artículo Open Access |
| id | wiley_oa_10_1111_bph_70021 |
| institution | Wiley Open Access |
| license_str_mv | http://creativecommons.org/licenses/by-nc/4.0/ |
| publishDate | 2025 |
| publisher | Wiley |
| record_format | wiley_oa |
| spellingShingle | ESG‐1‐60 and ESG‐1‐61: Novel dopamine D3 receptor‐preferring partial agonists/antagonists that inhibit cocaine taking and seeking in rodents Omar Soler‐Cedeño Bradley M. Keegan Hannah Alton Guo‐Hua Bi Emily Linz Caleb D. Vogt Emma S. Gogarnoiu Lei Shi Amy Hauck Newman Zheng‐Xiong Xi British Journal of Pharmacology ESG‐1‐60 and ESG‐1‐61: Novel dopamine D3 receptor‐preferring partial agonists/antagonists that inhibit cocaine taking and seeking in rodents Omar Soler‐Cedeño Bradley M. Keegan Hannah Alton Guo‐Hua Bi Emily Linz Caleb D. Vogt Emma S. Gogarnoiu Lei Shi Amy Hauck Newman Zheng‐Xiong Xi British Journal of Pharmacology AbstractBackground and PurposePreclinical studies suggest that highly selective dopamine D3 receptor (D3R) antagonists or partial agonists hold promise for treating substance use disorders. However, their limited effectiveness in reducing cocaine self‐administration is a major drawback. This study investigated whether cariprazine (D3 receptor‐preferring partial agonist) and its analogues ESG‐1‐60 and ESG‐1‐61 have enhanced efficacy in reducing cocaine‐taking and cocaine‐seeking behaviour.Experimental ApproachIn vitro BRET experiments were used to characterize the functional efficacies of cariprazine and its analogues. Intravenous cocaine self‐administration and reinstatement models were used to evaluate efficacy in reducing cocaine‐taking and cocaine‐seeking behaviour. Optical intracranial self‐stimulation (oICSS) procedures assessed effects on dopamine‐dependent behaviour. Open‐field locomotion, oral sucrose self‐administration and conditioned place‐preference were used to evaluate potential unwanted side effects.Key ResultsBRET functional assays indicated that cariprazine and ESG‐1‐60 are D3 receptor‐preferring partial agonists, while ESG‐1‐61 is a D3 receptor‐preferring antagonist/inverse agonist. All three compounds inhibited cocaine self‐administration under both fixed‐ratio and progressive‐ratio reinforcement schedules and reduced cocaine‐induced reinstatement of drug‐seeking behaviour in both male and female rats. The compounds did not alter locomotor behaviour but suppressed sucrose intake and dopamine‐dependent oICSS. Cariprazine and ESG‐1‐61 produced significant place aversion, while ESG‐1‐60 did not. Chronic administration of ESG‐1‐60 inhibited cocaine self‐administration.Conclusions and ImplicationsNovel D3 receptor‐preferring compounds ESG‐1‐60 and ESG‐1‐61 were highly effective in reducing cocaine‐taking and cocaine‐seeking, under various reinforcement conditions. ESG‐1‐60 warrants further investigation as a new pharmacotherapy for treating cocaine use disorder as it is effective in these models and lacks unwanted behavioural effects. 10.1111/bph.70021 http://creativecommons.org/licenses/by-nc/4.0/ |
| title | ESG‐1‐60 and ESG‐1‐61: Novel dopamine D3 receptor‐preferring partial agonists/antagonists that inhibit cocaine taking and seeking in rodents |
| topic | British Journal of Pharmacology |
| url | https://bpspubs.onlinelibrary.wiley.com/doi/10.1111/bph.70021 |