Potent and Selective Human 5-HT_2B Serotonin Receptor Antagonists: 4'-Cyano-(N)-methanocarba-adenosines by Synthetic Serendipity.

ABSTRACT: Rigidified nucleoside derivatives with (N)-methanocarba replacement of ribose have been repurposed as peripheral subtype-selective 5-HT_2B serotonin receptor antagonists for heart and lung fibrosis and intestinal/vascular conditions. 4'-Cyano derivative 40 (MRS8209; K_i, 4.27 nM) was 47-fold (human binding, but not rat and mouse) and 724-fold (functionally) selective at 5-HT_2BR, compared to antitarget 5-HT_2CR, and predicted to form a stable receptor complex using docking and molecular dynamics. 4'-Cyano substituents enhanced 5-HT_2BR affinity (typically 4-5-fold compared to 4'-CH₂OH), depending on an N⁶ group larger than methyl. Asymmetric N⁶ groups (4'-cyano-2-halo derivatives

SUBMITTER: Tosh DK 

PROVIDER: S-EPMC11715225 | biostudies-literature | 2024 Dec

REPOSITORIES: biostudies-literature