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

In this study, starting from our selective DR agonist (), we investigated the chemical space around the linker portion of the molecule via insertion of a hydroxyl substituent and ring-expansion of the -cyclopropyl moiety into a -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 ( ) by synthesizing and resolving bitopic analogues in all the and combinations of its 9-methoxy-3,4,4a,10b-tetrahydro-2,5-chromeno[4,3-][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 DR active and inactive states, and assist multitarget receptor recognition. Exploring stereochemical complexity and developing extended DR 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 DR agonism may be utilized in machine learning and artificial intelligence (AI)-based drug design, in the future.