Exception That Proves the Rule: Investigation of Privileged Stereochemistry in Designing Dopamine D₃R Bitopic Agonists

In this study, starting from our selective D3R agonist FOB02-04A (5), we investigated the chemical space around the linker portion of the molecule via insertion of a hydroxyl substituent and ring-expansion of the trans-cyclopropyl moiety into a trans-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 (+)-PD128907 ((+)-(4aR,10bR)-2)) by synthesizing and resolving bitopic analogues in all the cis and trans combinations of its 9-methoxy-3,4,4a,10b-tetrahydro-2H,5H-chromeno[4,3-b][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.