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The Significance of Chirality in Drug Design and Synthesis of Bitopic Ligands as D₃ Receptor (D₃R) Selective Agonists.

ABSTRACT: Because of the large degree of homology among dopamine D₂-like receptors, discovering ligands capable of discriminating between the D₂, D₃, and D₄ receptor subtypes remains a significant challenge. Previous work has exemplified the use of bitopic ligands as a powerful strategy in achieving subtype selectivity for agonists and antagonists alike. Inspired by the potential for chemical modification of the D₃ preferential agonists (+)-PD128,907 (1) and PF592,379 (2), we synthesized bitopic structures to further improve their D₃R selectivity. We found that the (2S,5S) conformation of scaffold 2 resulted in a privileged architecture with increased affinity and selectivity for the D₃R. In addition, a cyclopropyl moiety incorporated into the linker and full resolution of the chiral centers resulted in lead compound 53 and eutomer 53a that demonstrate significantly higher D₃R binding selectivities than the reference compounds. Moreover, the favorable metabolic stability in rat liver microsomes supports future studies in in vivo models of dopamine system dysregulation.

SUBMITTER: Battiti FO

PROVIDER: S-EPMC8272914 | biostudies-literature |

REPOSITORIES: biostudies-literature

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