Potent and\nSelective Human 5‑HT<sub>2B</sub> Serotonin Receptor Antagonists:\n4′-Cyano-(N)-methanocarba-adenosines\nby Synthetic Serendipity

Rigidified nucleoside derivatives with (N)-methanocarba\nreplacement\nof ribose have been repurposed as peripheral subtype-selective 5-HT<sub>2B</sub> serotonin receptor antagonists for heart and lung fibrosis\nand intestinal/vascular conditions. 4′-Cyano derivative <b>40</b> (MRS8209; <i>K<sub>i</sub></i>, 4.27 nM) was\n47-fold (human binding, but not rat and mouse) and 724-fold (functionally)\nselective at 5-HT<sub>2B</sub>R, compared to antitarget 5-HT<sub>2C</sub>R, and predicted to form a stable receptor complex using docking\nand molecular dynamics. 4′-Cyano substituents enhanced 5-HT<sub>2B</sub>R affinity (typically 4–5-fold compared to 4′-CH<sub>2</sub>OH), depending on an <i>N</i><sup>6</sup> group\nlarger than methyl. Asymmetric <i>N</i><sup>6</sup> groups\n(4′-cyano-2-halo derivatives <b>33</b>–<b>35</b> and <b>37</b>) provided potent 5-HT<sub>2B</sub>R <i>K<sub>i</sub></i> values (7–22 nM). A 4′-CH<sub>2</sub>CN substituent was less effective than 4′-CN at increasing\n5-HT<sub>2B</sub>R affinity, while a 4′-CHF<sub>2</sub> group\nproduced high 5-HT<sub>2B</sub> affinity/selectivity. A 2-benzylthio-adenine\ngroup with unsubstituted 6-NH<sub>2</sub> shifted the typical selectivity\npattern toward potent 5-HT<sub>2C</sub> binding. Thus, the SAR suggests\nthat <i>N</i><sup>6</sup>-cyclopentyl-4′-cyano modifications\nare promising, with an interdependence among the substituent positions.