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(2B)R, compared to antitarget 5-HT(2C)R, and predicted to form a stable receptor complex using docking and molecular dynamics. 4'-Cyano substituents enhanced 5-HT(2B)R affinity (typically 4-5-fold compared to 4'-CH(2)OH), depending on an N(6) group larger than methyl. Asymmetric N(6) groups (4'-cyano-2-halo derivatives 33-35 and 37) provided potent 5-HT(2B)R K(i) values (7-22 nM). A 4'-CH(2)CN substituent was less effective than 4'-CN at increasing 5-HT(2B)R affinity, while a 4'-CHF(2) group produced high 5-HT(2B) affinity/selectivity. A 2-benzylthio-adenine group with unsubstituted 6-NH(2) shifted the typical selectivity pattern toward potent 5-HT(2C) binding. Thus, the SAR suggests that N(6)-cyclopentyl-4'-cyano modifications are promising, with an interdependence among the substituent positions.