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Structure-Based Scaffold Repurposing for G Protein-Coupled Receptors: Transformation of Adenosine Derivatives into 5HT2B/5HT2C Serotonin Receptor Antagonists.

Abstract：

:Adenosine derivatives developed to activate adenosine receptors (ARs) revealed micromolar activity at serotonin 5HT2B and 5HT2C receptors (5HTRs). We explored the structure-activity relationship at 5HT2Rs and modeled receptor interactions in order to optimize affinity and simultaneously reduce AR affinity. Depending on N6 substitution, small 5'-alkylamide modification maintained 5HT2BR affinity, which was enhanced upon ribose substitution with rigid bicyclo[3.1.0]hexane (North (N)-methanocarba), e.g., N6-dicyclopropylmethyl 4'-CH2OH derivative 14 (Ki 11 nM). 5'-Methylamide 23 was 170-fold selective as antagonist for 5HT2BR vs 5HT2CR. 5'-Methyl 25 and ethyl 26 esters potently antagonized 5HT2Rs with moderate selectivity in comparison to ARs; related 6-N,N-dimethylamino analogue 30 was 5HT2R-selective. 5' position flexibility of substitution was indicated in 5HT2BR docking. Both 5'-ester and 5'-amide derivatives displayed in vivo t1/2 of 3-4 h. Thus, we used G protein-coupled receptor modeling to repurpose nucleoside scaffolds in favor of binding at nonpurine receptors as novel 5HT2R antagonists, with potential for cardioprotection, liver protection, or central nervous system activity.

journal_name

J Med Chem

journal_title

Journal of medicinal chemistry

authors

Tosh DK,Ciancetta A,Warnick E,Crane S,Gao ZG,Jacobson KA

doi

10.1021/acs.jmedchem.6b01183

subject

Has Abstract

pub_date

2016-12-22 00:00:00

pages

11006-11026

issue

24

eissn

0022-2623

issn

1520-4804

journal_volume

59

pub_type

杂志文章

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