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

Rigidified nucleoside derivatives with (N)-methanocarba replacement of ribose have been repurposed as peripheral subtype-selective 5-HT serotonin receptor antagonists for heart and lung fibrosis and intestinal/vascular conditions. 4'-Cyano derivative (MRS8209; , 4.27 nM) was 47-fold (human binding, but not rat and mouse) and 724-fold (functionally) selective at 5-HTR, compared to antitarget 5-HTR, and predicted to form a stable receptor complex using docking and molecular dynamics. 4'-Cyano substituents enhanced 5-HTR affinity (typically 4-5-fold compared to 4'-CHOH), depending on an group larger than methyl. Asymmetric groups (4'-cyano-2-halo derivatives - and ) provided potent 5-HTR values (7-22 nM). A 4'-CHCN substituent was less effective than 4'-CN at increasing 5-HTR affinity, while a 4'-CHF group produced high 5-HT affinity/selectivity. A 2-benzylthio-adenine group with unsubstituted 6-NH shifted the typical selectivity pattern toward potent 5-HT binding. Thus, the SAR suggests that -cyclopentyl-4'-cyano modifications are promising, with an interdependence among the substituent positions.