Modifications on the Amino-3,5-dicyanopyridine Core To Obtain Multifaceted Adenosine Receptor Ligands with Antineuropathic Activity

Betti Marco; Catarzi Daniela; Varano Flavia; Falsini Matteo; Varani Katia; Vincenzi Fabrizio; Pasquini Silvia; Mannelli Lorenzo di Cesare; Ghelardini Carla; Lucarin Elena; Dal Ben Diego; Spinaci Andrea; Bartolucci Gianluca; Menicatti Marta; Colotta Vittoria

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Modifications on the Amino-3,5-dicyanopyridine Core To Obtain Multifaceted Adenosine Receptor Ligands with Antineuropathic Activity

机译：氨基-3,5-二氰基吡啶核的修饰，得到抗脉冲性活性的多型腺苷受体配体

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A new series of amino-3,5-dicyanopyridines (1-31) was synthesized and biologically evaluated in order to further investigate the potential of this scaffold to obtain adenosine receptor (AR) ligands. In general, the modifications performed have led to compounds having high to good human (h) A(1)AR affinity and an inverse agonist profile. While most of the compounds are hA(1)AR-selective, some derivatives behave as mixed hA(1)AR inverse agonists/A(2A) and A(2B) AR antagonists. The latter compounds (9-12) showed that they reduce oxaliplatin-induced neuropathic pain by a mechanism involving the alpha7 subtype of nAchRs, similar to the nonselective AR antagonist caffeine, taken as the reference compound. Along with the pharmacological evaluation, chemical stability of methyl 3-(((6-amino-3,5-dicyano-4-(furan-2-yl)pyridin-2-yl)sulfanyl)methyl)benzoate 10 was assessed in plasma matrices (rat and human), and molecular modeling studies were carried out to better rationalize the available structure-activity relationships.

机译：合成新的一系列氨基-3,5-二氰基吡啶（1-31），并在生物学评价中，以进一步研究该支架的潜力，得到腺苷受体（Ar）配体。通常，所进行的修饰导致具有高于良好的人（h）A（1）Ar亲和力和反向激动剂轮廓的化合物。虽然大多数化合物是HA（1）Ar选择性，但一些衍生物表现为混合HA（1）反向激动剂/ A（2A）和A（2B）Ar拮抗剂。后一种化合物（9-12）表明，它们通过涉及NACHRS的α7亚型的机制减少了奥沙利铂诱导的神经性疼痛，类似于非选择性AR拮抗剂咖啡因，作为参考化合物。随着药理评价，甲基3的化学稳定性 - （（（6-氨基-3,5-二氰基-4-（呋喃-2-基）吡啶-2-基）硫基）甲基）苯甲酸甲酯10在血浆中评估进行基质（大鼠和人），并进行分子建模研究以更好地合理地利用可用的结构 - 活性关系。

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《Journal of Medicinal Chemistry》 |2019年第15期|共19页
作者
Betti Marco; Catarzi Daniela; Varano Flavia; Falsini Matteo; Varani Katia; Vincenzi Fabrizio; Pasquini Silvia; Mannelli Lorenzo di Cesare; Ghelardini Carla; Lucarin Elena; Dal Ben Diego; Spinaci Andrea; Bartolucci Gianluca; Menicatti Marta; Colotta Vittoria;
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作者单位

Univ Firenze Sez Farmaceut &

Nutraceut Area Farmaco &

Salute Bambino Dipartimento Neurosci Psicol Via Ugo Schiff 6 I-50019 Sesto Fiorentino Italy;

Univ Firenze Sez Farmaceut &

Nutraceut Area Farmaco &

Salute Bambino Dipartimento Neurosci Psicol Via Ugo Schiff 6 I-50019 Sesto Fiorentino Italy;

Univ Firenze Sez Farmaceut &

Nutraceut Area Farmaco &

Salute Bambino Dipartimento Neurosci Psicol Via Ugo Schiff 6 I-50019 Sesto Fiorentino Italy;

Univ Firenze Sez Farmaceut &

Nutraceut Area Farmaco &

Salute Bambino Dipartimento Neurosci Psicol Via Ugo Schiff 6 I-50019 Sesto Fiorentino Italy;

Univ Ferrara Sez Farmacol Dipartimento Sci Med Via Fossato Mortara 17-19 I-44121 Ferrara Italy;

Univ Ferrara Sez Farmacol Dipartimento Sci Med Via Fossato Mortara 17-19 I-44121 Ferrara Italy;

Univ Ferrara Sez Farmacol Dipartimento Sci Med Via Fossato Mortara 17-19 I-44121 Ferrara Italy;

Univ Firenze Sez Farmacol &

Tossicol Area Farmaco &

Salute Bambino Dipartimento Neurosci Psicol Viale Pieraccini 6 I-50139 Florence Italy;

Univ Firenze Sez Farmacol &

Tossicol Area Farmaco &

Salute Bambino Dipartimento Neurosci Psicol Viale Pieraccini 6 I-50139 Florence Italy;

Univ Firenze Sez Farmacol &

Tossicol Area Farmaco &

Salute Bambino Dipartimento Neurosci Psicol Viale Pieraccini 6 I-50139 Florence Italy;

Univ Camerino Scuola Sci Farmaco &

Prod Salute Via S Agostino 1 I-62032 Camerino Macerata Italy;

Univ Camerino Scuola Sci Farmaco &

Prod Salute Via S Agostino 1 I-62032 Camerino Macerata Italy;

Univ Firenze Sez Farmaceut &

Nutraceut Area Farmaco &

Salute Bambino Dipartimento Neurosci Psicol Via Ugo Schiff 6 I-50019 Sesto Fiorentino Italy;

Univ Firenze Sez Farmaceut &

Nutraceut Area Farmaco &

Salute Bambino Dipartimento Neurosci Psicol Via Ugo Schiff 6 I-50019 Sesto Fiorentino Italy;

Univ Firenze Sez Farmaceut &

Nutraceut Area Farmaco &

Salute Bambino Dipartimento Neurosci Psicol Via Ugo Schiff 6 I-50019 Sesto Fiorentino Italy;

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1. Modifications on the Amino-3,5-dicyanopyridine Core To Obtain Multifaceted Adenosine Receptor Ligands with Antineuropathic Activity [J] . Betti Marco, Catarzi Daniela, Varano Flavia, Journal of Medicinal Chemistry . 2019,第15期

机译：氨基-3,5-二氰基吡啶核的修饰，得到抗脉冲性活性的多型腺苷受体配体
2. Chemical modifications of striatal A_(2A) adenosine receptors: a possible role for tyrosine at the ligand binding sites [J] . Claudia Martini, Letizia Trincavelli, Antonio Lucacchini Biochimica et biophysica acta. Biomembranes . 1997,第1期

机译：纹状体A_（2A）腺苷受体的化学修饰：酪氨酸在配体结合位点的可能作用
3. Structure-activity relationships of truncated C2- or C8-substituted adenosine derivatives as dual acting A _(2A) and A _3 adenosine receptor ligands [J] . Hou X., Majik M.S., Kim K., Journal of Medicinal Chemistry . 2012,第1期

机译：截短的C2或C8取代的腺苷衍生物作为双作用A _（2A）和A _3腺苷受体配体的结构活性关系
4. Insights into binding modes of adenosine A2B antagonists with ligand-based and receptor-based methods [C] . Feixiong Cheng, Zhejun Xu, Guixia Liu, ICMSI;International conference of molecular simulations and applied informatics technologies . 2010

机译：基于配体和受体的方法洞察腺苷A2B拮抗剂的结合模式
5. Receptor-receptor, ligand, and membrane interactions of the adenosine A2A receptor [D] . McNeely, Patrick M. 2016

机译：腺苷A2A受体的受体 - 受体，配体和膜相互作用
6. Polypharmacology of N6-(3-Iodobenzyl)adenosine-5′-N-methyluronamide (IB-MECA) and Related A3 Adenosine Receptor Ligands: Peroxisome Proliferator Activated Receptor (PPAR) γ Partial Agonist and PPARδ Antagonist Activity Suggests Their Antidiabetic Potential [O] . Jinha Yu, Seyeon Ahn, Hee Jin Kim, -1

机译：N6-（3-碘苄基）腺苷-5-N-甲基脲酰胺（IB-MECA）和相关的A3腺苷受体配体的多药理学：过氧化物酶体增殖物激活受体（PPAR）γ部分激动剂和PPARδ拮抗剂的活性表明其抗糖尿病潜力
7. Modifications on the Amino-3,5-dicyanopyridine Core To Obtain Multifaceted Adenosine Receptor Ligands with Antineuropathic Activity [O] . -1

机译：氨基-3,5-二氰基吡啶核的修饰，得到抗脉冲性活性的多型腺苷受体配体
8. Structural and Functional Analysis of HIV-1 Coreceptors: Roles of Charged Residues and Posttranslational Modifications on Coreceptor Activity [R] . Chabot, D. J. 2000

机译：HIV-1共同受体的结构和功能分析：带电残基和翻译后修饰对受体活性的影响

Modifications on the Amino-3,5-dicyanopyridine Core To Obtain Multifaceted Adenosine Receptor Ligands with Antineuropathic Activity

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