Rigidified nucleoside derivatives with (N)-methanocarba replacement of ribose have been repurposed as peripheral subtype-selective 5-HT2B serotonin receptor antagonists for heart and lung fibrosis and intestinal/vascular conditions. 4'-Cyano derivative 40 (MRS8209; Ki, 4.27 nM) was 47-fold (human binding, but not rat and mouse) and 724-fold (functionally) selective at 5-HT2BR, compared to antitarget 5-HT2CR, and predicted to form a stable receptor complex using docking and molecular dynamics. 4'-Cyano substituents enhanced 5-HT2BR 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 33-35 and 37) provided potent 5-HT2BR Ki values (7-22 nM). A 4'-CH2CN substituent was less effective than 4'-CN at increasing 5-HT2BR affinity, while a 4'-CHF2 group produced high 5-HT2B affinity/selectivity. A 2-benzylthio-adenine group with unsubstituted 6-NH2 shifted the typical selectivity pattern toward potent 5-HT2C binding. Thus, the SAR suggests that N6-cyclopentyl-4'-cyano modifications are promising, with an interdependence among the substituent positions.