Potent and Selective Human 5-HT 2B Serotonin Receptor Antagonists: 4'-Cyano-(N)-methanocarba-adenosines by Synthetic Serendipity.

Autor:	Tosh DK; Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institutes of Health, Bethesda, Maryland 20892, United States., Pavan M; Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institutes of Health, Bethesda, Maryland 20892, United States., Clark AA; Department of Cell Biology, Neurobiology, and Anatomy, Neuroscience Research Center, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, Wisconsin 53226, United States., Lammers J; Department of Cell Biology, Neurobiology, and Anatomy, Neuroscience Research Center, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, Wisconsin 53226, United States., Villano S; Department of Neuroscience, Psychology, Drug Research and Child Health (NEUROFARBA), Section of Pharmacology, University of Florence, Viale Gaetano Pieraccini, 6, Florence 50139, Italy., Marri S; Department of Neuroscience, Psychology, Drug Research and Child Health (NEUROFARBA), Section of Pharmacology, University of Florence, Viale Gaetano Pieraccini, 6, Florence 50139, Italy., Sgambellone S; Department of Neuroscience, Psychology, Drug Research and Child Health (NEUROFARBA), Section of Pharmacology, University of Florence, Viale Gaetano Pieraccini, 6, Florence 50139, Italy., Choi S; Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institutes of Health, Bethesda, Maryland 20892, United States., Lee J; Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institutes of Health, Bethesda, Maryland 20892, United States., Ivancich MS; Department of Cell Biology, Neurobiology, and Anatomy, Neuroscience Research Center, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, Wisconsin 53226, United States., Bock HA; Department of Cell Biology, Neurobiology, and Anatomy, Neuroscience Research Center, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, Wisconsin 53226, United States., Campbell RG; Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institutes of Health, Bethesda, Maryland 20892, United States., Lewicki SA; Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institutes of Health, Bethesda, Maryland 20892, United States., Levitan IM; Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institutes of Health, Bethesda, Maryland 20892, United States., Chen E; Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institutes of Health, Bethesda, Maryland 20892, United States., Liu N; Mouse Metabolism Core, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892, United States., Demby T; Mouse Metabolism Core, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892, United States., Gavrilova O; Mouse Metabolism Core, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892, United States., Gao ZG; Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institutes of Health, Bethesda, Maryland 20892, United States., Lucarini L; Department of Neuroscience, Psychology, Drug Research and Child Health (NEUROFARBA), Section of Pharmacology, University of Florence, Viale Gaetano Pieraccini, 6, Florence 50139, Italy., McCorvy JD; Department of Cell Biology, Neurobiology, and Anatomy, Neuroscience Research Center, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, Wisconsin 53226, United States., Jacobson KA; Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institutes of Health, Bethesda, Maryland 20892, United States.
Jazyk:	angličtina
Zdroj:	Journal of medicinal chemistry [J Med Chem] 2024 Dec 12; Vol. 67 (23), pp. 21264-21291. Date of Electronic Publication: 2024 Nov 26.
DOI:	10.1021/acs.jmedchem.4c02174
Abstrakt:	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.
Databáze:	MEDLINE
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