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

Abstract

Adenosine derivatives developed to activate adenosine receptors (ARs) revealed µM 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, 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 GPCR modeling to repurpose nucleoside scaffolds in favor of binding at nonpurine receptors, as novel 5HT2R antagonists, with potential for cardioprotection, liver protection or CNS activity.

Scaffold Repurposing of Nucleosides (Adenosine Receptor Agonists): Enhanced Activity at the Human Dopamine and Norepinephrine Sodium Symporters

“…However, the in vivo stability of the corresponding 5′-ester group was shown for another member of this series of rigid (N)-methanocarba nucleosides in the context of 5HT 2B R antagonists. 28 Also, amide derivatives in the present set of compounds, such as orally administered 1 , were shown to be bioavailable and have long lasting in vivo effects in mice and are not rapidly metabolized. 2,19 These rigid nucleosides, such as 1 , typically do not inhibit cytochrome P450 (5 isozymes) and are stable in the presence of liver microsomes, plasma and simulated body fluids.…”

“…40 Although the ester derivatives 9 - 16 bound at the hA 3 AR with K i values of 5 - 43 nM ( 13 : 169 nM), two of them ( 9 and 13 ) were shown to have little or no ability to activate the receptor, suggesting that they may be A 3 AR antagonists. Similarly, several weakly binding adenosine 5′-ester derivatives (methanocarba series) were shown to be either partial agonist or antagonist at the hA 3 AR 28 ; thus, 5′-amides but not 5′-esters tend to fully activate the hA 3 AR.…”

Polypharmacology of conformationally locked methanocarba nucleosides

“…Structures of methanocarba nucleosides that interact with: (a) P2Y 1 R, (b) ENT1, (c) polymerases and kinases [35,45,62]. …”

Structure‐Based Design and Synthesis of Fluorene Derivatives as Novel RORγt Inverse Agonists

“…The stability assay of compounds 10 -15 in rat liver microsomes was performed as previously described. [33] In vitro Blood-Brain Barrier Permeability…”