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

Adenosine derivatives developed to activate adenosine receptors (ARs) revealed micromolar activity at serotonin 5HT_2B and 5HT_2C 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 5HT_2BR 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 (K_i 11 nM). 5'-Methylamide 23 was 170-fold selective as antagonist for 5HT_2BR vs 5HT_2CR. 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 5HT_2BR docking. Both 5'-ester and 5'-amide derivatives displayed in vivo t_1/2 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.