Structure-Based Scaffold Repurposing for G Protein-Coupled Receptors: Transformation of Adenosine Derivatives into 5HT_2B/5HT_2C Serotonin Receptor Antagonists

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.