Truncated (N)-Methanocarba Nucleosides as Partial Agonists at Mouse and Human A3 Adenosine Receptors: Affinity Enhancement by N6-(2-Phenylethyl) Substitution.,Journal of Medicinal Chemistry

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Truncated (N)-Methanocarba Nucleosides as Partial Agonists at Mouse and Human A3 Adenosine Receptors: Affinity Enhancement by N6-(2-Phenylethyl) Substitution.
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2020-04-09 , DOI: 10.1021/acs.jmedchem.0c00235
Dilip K Tosh , Veronica Salmaso , Harsha Rao , Amelia Bitant ₁ , Courtney L Fisher ₁ , David I Lieberman , Helmut Vorbrüggen ₂ , Marc L Reitman , Oksana Gavrilova , Zhan-Guo Gao , John A Auchampach ₁ , Kenneth A Jacobson

Affiliation

Dopamine-derived N6-substituents, compared to N6-(2-phenylethyl), in truncated (N)-methanocarba (bicyclo[3.1.0]hexyl) adenosines favored high A3 adenosine receptor (AR) affinity/selectivity, e.g., C2-phenylethynyl analogue 15 (MRS7591, Ki = 10.9/17.8 nM, at human/mouse A3AR). 15 was a partial agonist in vitro (hA3AR, cAMP inhibition, 31% Emax; mA3AR, [35S]GTP-γ-S binding, 16% Emax) and in vivo and also antagonized hA3AR in vitro. Distal H-bonding substitutions of the N6-(2-phenylethyl) moiety particularly enhanced mA3AR affinity by polar interactions with the extracellular loops, predicted using docking and molecular dynamics simulation with newly constructed mA3AR and hA3AR homology models. These hybrid models were based on an inactive antagonist-bound hA1AR structure for the upper part of TM2 and an agonist-bound hA2AAR structure for the remaining TM portions. These species-independent A3AR-selective nucleosides are low efficacy partial agonists and novel, nuanced modulators of the A3AR, a drug target of growing interest.

中文翻译：

截短 (N)-Methanocarba 核苷作为小鼠和人 A3 腺苷受体的部分激动剂：通过 N6-(2-苯乙基) 取代增强亲和力。

与 N6-(2-苯乙基) 相比，截短的 (N)-亚甲基卡巴（双环[3.1.0]己基）腺苷中多巴胺衍生的 N6-取代基有利于高 A3 腺苷受体 (AR) 亲和力/选择性，例如 C2-苯乙炔基类似物 15（MRS7591，Ki = 10.9/17.8 nM，人/小鼠 A3AR）。 15在体外（hA3AR，cAMP抑制，31% Emax；mA3AR，[35S]GTP-γ-S结合，16% Emax）和体内是部分激动剂，并且还在体外拮抗hA3AR。 N6-(2-苯乙基)部分的远端氢键取代通过与细胞外环的极性相互作用特别增强了mA3AR的亲和力，这是使用新构建的mA3AR和hA3AR同源模型的对接和分子动力学模拟预测的。这些混合模型基于 TM2 上部的非活性拮抗剂结合 hA1AR 结构和其余 TM 部分的激动剂结合 hA2AAR 结构。这些与物种无关的 A3AR 选择性核苷是低效部分激动剂和新型、细致的 A3AR 调节剂，A3AR 是人们日益关注的药物靶点。

更新日期：2020-04-24

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