2. Academic Validation
  3. Potent and Selective Human 5-HT2B Serotonin Receptor Antagonists: 4'-Cyano-(N)-methanocarba-adenosines by Synthetic Serendipity

Potent and Selective Human 5-HT2B Serotonin Receptor Antagonists: 4'-Cyano-(N)-methanocarba-adenosines by Synthetic Serendipity

  • J Med Chem. 2024 Dec 12;67(23):21264-21291. doi: 10.1021/acs.jmedchem.4c02174.
Dilip K Tosh 1,  Matteo Pavan 1,  Allison A Clark 2,  Josie Lammers 2,  Serafina Villano 3,  Silvia Marri 3,  Silvia Sgambellone 3,  Suebin Choi 1,  Jihyun Lee 1,  Marko S Ivancich 2,  Hailey A Bock 2,  Ryan G Campbell 1,  Sarah A Lewicki 1,  Ian M Levitan 1,  Eric Chen 1,  Naili Liu 4,  Tamar Demby 4,  Oksana Gavrilova 4,  Zhan-Guo Gao 1,  Laura Lucarini 3,  John D McCorvy 2,  Kenneth A Jacobson 1
Affiliations

Affiliations

  • 1 Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institutes of Health, Bethesda, Maryland 20892, United States.
  • 2 Department of Cell Biology, Neurobiology, and Anatomy, Neuroscience Research Center, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, Wisconsin 53226, United States.
  • 3 Department of Neuroscience, Psychology, Drug Research and Child Health (NEUROFARBA), Section of Pharmacology, University of Florence, Viale Gaetano Pieraccini, 6, Florence 50139, Italy.
  • 4 Mouse Metabolism Core, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892, United States.
PMID: 39589936 DOI: 10.1021/acs.jmedchem.4c02174
Abstract

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.

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