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
Date
11/26/2024Pubmed ID
39589936Pubmed Central ID
PMC11715225DOI
10.1021/acs.jmedchem.4c02174Scopus ID
2-s2.0-85210269617 (requires institutional sign-in at Scopus site) 7 CitationsAbstract
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.
Author List
Tosh DK, Pavan M, Clark AA, Lammers J, Villano S, Marri S, Sgambellone S, Choi S, Lee J, Ivancich MS, Bock HA, Campbell RG, Lewicki SA, Levitan IM, Chen E, Liu N, Demby T, Gavrilova O, Gao ZG, Lucarini L, McCorvy JD, Jacobson KAAuthor
John McCorvy PhD Associate Professor in the Cell Biology Neurobiology and Anatomy department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AnimalsHumans
Mice
Molecular Docking Simulation
Nitriles
Rats
Receptor, Serotonin, 5-HT2B
Serotonin 5-HT2 Receptor Antagonists
Structure-Activity Relationship
