biostudies-literatureBattiti FOIntramural NIH HHSNational Institute on Drug Abuse1956-1964https://www.ebi.ac.uk/biostudies/studies/S-EPMC7549273biostudies-literatureUnknown11(10)In this study, starting from our selective D₃R agonist <b>FOB02-04A</b> (<b>5</b>), we investigated the chemical space around the linker portion of the molecule via insertion of a hydroxyl substituent and ring-expansion of the <i>trans</i>-cyclopropyl moiety into a <i>trans</i>-cyclohexyl scaffold. Moreover, to further elucidate the importance of the primary pharmacophore stereochemistry in the design of bitopic ligands, we investigated the chiral requirements of <b>(+)-PD128907</b> (<b>(+)-(4a</b> <i>R</i> <b>,10b</b> <i>R</i> <b>)-2)</b>) by synthesizing and resolving bitopic analogues in all the <i>cis</i> and <i>trans</i> combinations of its 9-methoxy-3,4,4a,10b-tetrahydro-2<i>H</i>,5<i>H</i>-chromeno[4,3-<i>b</i>][1,4] oxazine scaffold. Despite the lack of success in obtaining new analogues with improved biological profiles, in comparison to our current leads, a "negative" result due to a poor or simply not improved biological profile is fundamental toward better understanding chemical space and optimal stereochemistry for target recognition. Herein, we identified essential structural information to understand the differences between orthosteric and bitopic ligand-receptor binding interactions, discriminate D₃R active and inactive states, and assist multitarget receptor recognition. Exploring stereochemical complexity and developing extended D₃R SAR from this new library complements previously described SAR and inspires future structural and computational biology investigation. Moreover, the expansion of chemical space characterization for D₃R agonism may be utilized in machine learning and artificial intelligence (AI)-based drug design, in the future.ACS medicinal chemistry lettersException That Proves the Rule: Investigation of Privileged Stereochemistry in Designing Dopamine D₃R Bitopic Agonists.PMC7549273Z01 DA000424Z1A DA000609ZIA DA000609Z1A DA000424Battiti FONewman AHBonifazi AfalseException That Proves the Rule: Investigation of Privileged Stereochemistry in Designing Dopamine D₃R Bitopic Agonists.In this study, starting from our selective D₃R agonist <b>FOB02-04A</b> (<b>5</b>), we investigated the chemical space around the linker portion of the molecule via insertion of a hydroxyl substituent and ring-expansion of the <i>trans</i>-cyclopropyl moiety into a <i>trans</i>-cyclohexyl scaffold. Moreover, to further elucidate the importance of the primary pharmacophore stereochemistry in the design of bitopic ligands, we investigated the chiral requirements of <b>(+)-PD128907</b> (<b>(+)-(4a</b> <i>R</i> <b>,10b</b> <i>R</i> <b>)-2)</b>) by synthesizing and resolving bitopic analogues in all the <i>cis</i> and <i>trans</i> combinations of its 9-methoxy-3,4,4a,10b-tetrahydro-2<i>H</i>,5<i>H</i>-chromeno[4,3-<i>b</i>][1,4] oxazine scaffold. Despite the lack of success in obtaining new analogues with improved biological profiles, in comparison to our current leads, a "negative" result due to a poor or simply not improved biological profile is fundamental toward better understanding chemical space and optimal stereochemistry for target recognition. Herein, we identified essential structural information to understand the differences between orthosteric and bitopic ligand-receptor binding interactions, discriminate D₃R active and inactive states, and assist multitarget receptor recognition. Exploring stereochemical complexity and developing extended D₃R SAR from this new library complements previously described SAR and inspires future structural and computational biology investigation. Moreover, the expansion of chemical space characterization for D₃R agonism may be utilized in machine learning and artificial intelligence (AI)-based drug design, in the future.2020-01-01T00:00:00Z2020 Oct2024-02-15T17:24:26.173Z2022-02-11T11:52:29.833ZS-EPMC75492733306217910.1021/acsmedchemlett.9b00660