Adenosine derivatives developed to activate adenosine receptors (ARs) revealed µM off-target activity at serotonin 5HT2B and 5HT2C receptors (5HTRs). We explored the SAR at 5HT2Rs and modeled receptor interactions in order to optimize affinity and simultaneously reduce AR affinity. Depending on N6 substitution, a small 5'-alkylamide modification of ribose maintained weak 5HT2BR affinity, which was enhanced upon ribose substitution with a rigid bicyclo[3.1.0]hexane (North (N)-methanocarba) moiety, i.e. N6-dicyclopropylmethyl 4'-CH2OH derivative MRS7134 (Ki 11 nM). Corresponding 5'-methylamide MRS7185 was 12-fold selective for 5HT2BR vs. 5HT2CR. Alkyl ester MRS7221 potently antagonized 5HT2Rs with moderate selectivity in comparison to ARs; related 6-N,N-dimethylamino analogue MRS7248 was 5HT2R-selective. 5'-ω- position flexibility of substitution in (N)-methanocarba nucleosides was indicated in the docking mode at 5HT2CR but not ARs. Consistent with predictions, 5'-ω-aminoalkylamides displayed moderate 5HT2R affinity with reduced AR affinity. Thus, we have used GPCR modeling to repurpose nucleoside scaffolds in favor of binding at an off-target receptor to provide novel 5HT2R antagonists, which can be explored for cardioprotection, liver protection or CNS activity.

Repurposing for G-protein couple receptors by structure-based discovery: Transformation of adenosine derivatives into 5HT2B/5HT2C serotonin receptor antagonists

253rd National Meeting (2017)

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