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 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.

为激活腺苷受体（adenosine receptors, ARs）而开发的腺苷衍生物，在血清素5HT2B及5HT2C受体（5-羟色胺受体，5HTRs）上展现出微摩尔级的生物活性。本研究针对5HT2受体开展构效关系研究，并对受体相互作用进行分子建模，以期优化其对5HT2受体的亲和力，同时降低对腺苷受体的结合亲和力。根据N6位取代基的不同，5′位小型烷基酰胺修饰可保留对5HT2BR的亲和力；若将核糖替换为刚性双环[3.1.0]己烷（北（N）-甲烷并环，North (N)-methanocarba），则该亲和力可得到显著增强，例如N6-二环丙基甲基-4′-CH2OH衍生物14（抑制常数Ki=11 nM）。5′-甲基酰胺衍生物23对5HT2BR的拮抗选择性相较于5HT2CR高达170倍。5′-甲酯25与乙酯26可强效拮抗5HT2受体，相较于腺苷受体表现出中等程度的选择性；与之相关的6-N,N-二甲基氨基类似物30则对5HT2受体具有良好选择性。5HT2BR分子对接实验结果表明，其5′位取代基具有一定的结构柔性。所有5′-酯类与5′-酰胺类衍生物的体内半衰期均为3~4小时。综上，本研究借助G蛋白偶联受体建模技术，将核苷骨架重新定向开发为靶向非嘌呤受体的新型5HT2受体拮抗剂，其在心脏保护、肝脏保护或中枢神经系统活性调控方面具备潜在应用前景。