Synthesis, pharmacological and structural studies of 5-substituted-3-(1-arylmethyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indoles as multi-target ligands of aminergic GPCRs.,European Journal of Medicinal Chemistry

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Synthesis, pharmacological and structural studies of 5-substituted-3-(1-arylmethyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indoles as multi-target ligands of aminergic GPCRs.
European Journal of Medicinal Chemistry ( IF 6.0 ) Pub Date : 2019-07-20 , DOI: 10.1016/j.ejmech.2019.07.050
Magda Kondej ₁ , Tomasz M Wróbel ₂ , Andrea G Silva ₃ , Piotr Stępnicki ₁ , Oliwia Koszła ₁ , Ewa Kędzierska ₄ , Agata Bartyzel ₅ , Grażyna Biała ₄ , Dariusz Matosiuk ₁ , Maria I Loza ₃ , Marián Castro ₃ , Agnieszka A Kaczor ₆

Affiliation

Department of Synthesis and Chemical Technology of Pharmaceutical Substances, Faculty of Pharmacy with Division of Medical Analytics, Medical University of Lublin, 4A Chodźki St., PL-20093, Lublin, Poland.
Department of Synthesis and Chemical Technology of Pharmaceutical Substances, Faculty of Pharmacy with Division of Medical Analytics, Medical University of Lublin, 4A Chodźki St., PL-20093, Lublin, Poland; Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, 2100, Copenhagen, Denmark.
Department of Pharmacology, Universidade de Santiago de Compostela, Center for Research in Molecular Medicine and Chronic Diseases (CIMUS), Avda de Barcelona, Santiago de Compostela, E-15782, Spain.
Department of Pharmacology and Pharmacodynamics, Faculty of Pharmacy with Division of Medical Analytics, Medical University of Lublin, 4A Chodźki St., PL-20093, Lublin, Poland.
Department of General and Coordination Chemistry, Maria Curie-Skłodowska University, M. Curie-Skłodowskiej Sq. 2, PL-20031, Lublin, Poland.
Department of Synthesis and Chemical Technology of Pharmaceutical Substances, Faculty of Pharmacy with Division of Medical Analytics, Medical University of Lublin, 4A Chodźki St., PL-20093, Lublin, Poland; School of Pharmacy, University of Eastern Finland, Yliopistonranta 1, P.O. Box 1627, FI-70211, Kuopio, Finland.

Schizophrenia is a complex disease with not fully understood pathomechanism, involving many neurotransmitters and their receptors. This is why it is best treated with multi-target drugs, such as second generation antipsychotics. Here we present 5-substituted-3-(1-arylmethyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indoles (1-20) which are ligands of dopamine D2 and serotonin 5-HT1A and 5-HT2A receptors and display affinity in the nanomolar range. These compounds were designed as modifications of the virtual hit experimentally confirmed, D2AAK1, and synthesized from indole or 5-alkoxyindoles and N-substituted piperidin-4-ones in methanol in the presence of potassium hydroxide. Compound 9 was subjected to X-ray studies and it crystallizes in the centrosymmetric monoclinic space group P21/c with one molecule in an asymmetric unit. Three most potent compounds (5, 9 and 17) turned out to be antagonists of both D2 and 5-HT2A receptors what is beneficial for their potential application as antipsychotics. Compound 5 was subjected to behavioral studies and exhibited antipsychotic, pro-cognitive and antidepressant activity in appropriate mice models. Structure-activity relationships for compounds 1-20 were rationalized using molecular docking. It was found that, in general, bulky C5-alkoxy substituents at the indole moiety are not favorable as they direct towards aqueous environment of the extracellular vestibule. Keywords: antipsychotics; behavioral studies, G protein-coupled receptors; indole derivatives; multi-target compounds; schizophrenia.

中文翻译：

5取代的3-（1-芳甲基-1,2,3,6-四氢吡啶-4--4-基）-1H-吲哚作为胺能GPCR的多靶点配体的合成，药理和结构研究。

精神分裂症是一种复杂的疾病，其发病机理尚未完全明了，涉及许多神经递质及其受体。这就是为什么最好用多靶点药物（例如第二代抗精神病药）对其进行治疗的原因。在这里，我们介绍了多巴胺D2和5-羟色胺5-HT1A和5的配体5-取代-3-（1-芳甲基-1,2,3,6-四氢吡啶-4--4-基）-1H-吲哚（1-20） -HT2A受体在纳摩尔范围内显示亲和力。这些化合物被设计为经实验证实的虚拟命中化合物D2AAK1的修饰，并在甲醇中，在氢氧化钾的存在下，由吲哚或5-烷氧基吲哚和N-取代的哌啶-4-酮合成。对化合物9进行了X射线研究，它在不对称单元中有一个分子的中心对称单斜空间群P21 / c中结晶。三种最有效的化合物（5、9和17）被证明是D2和5-HT2A受体的拮抗剂，这对于它们作为抗精神病药的潜在应用是有益的。对化合物5进行了行为研究，并在适当的小鼠模型中显示出抗精神病药，促认知药和抗抑郁药的活性。使用分子对接使化合物1-20的结构活性关系合理化。已经发现，通常，在吲哚部分的大体积C5-烷氧基取代基是不利的，因为它们直接指向细胞外前庭的水性环境。关键词：抗精神病药；抗精神病药行为研究，G蛋白偶联受体；吲哚衍生物多目标化合物精神分裂症。9和17）既是D2受体又是5-HT2A受体的拮抗剂，这对于它们作为抗精神病药的潜在应用是有益的。对化合物5进行了行为研究，并在适当的小鼠模型中显示出抗精神病药，促认知药和抗抑郁药的活性。使用分子对接使化合物1-20的结构活性关系合理化。已经发现，通常，在吲哚部分的大体积C5-烷氧基取代基是不利的，因为它们直接指向细胞外前庭的水性环境。关键词：抗精神病药；抗精神病药行为研究，G蛋白偶联受体；吲哚衍生物多目标化合物精神分裂症。9和17）既是D2受体又是5-HT2A受体的拮抗剂，这对于它们作为抗精神病药的潜在应用是有益的。对化合物5进行了行为研究，并在适当的小鼠模型中显示出抗精神病药，促认知药和抗抑郁药的活性。使用分子对接使化合物1-20的结构活性关系合理化。已经发现，通常，在吲哚部分的大体积C5-烷氧基取代基是不利的，因为它们直接指向细胞外前庭的水性环境。关键词：抗精神病药；抗精神病药行为研究，G蛋白偶联受体；吲哚衍生物多目标化合物精神分裂症。使用分子对接使化合物1-20的结构活性关系合理化。已经发现，通常，在吲哚部分的大体积C5-烷氧基取代基是不利的，因为它们直接指向细胞外前庭的水性环境。关键词：抗精神病药；抗精神病药行为研究，G蛋白偶联受体；吲哚衍生物多目标化合物精神分裂症。使用分子对接使化合物1-20的结构活性关系合理化。已经发现，通常，在吲哚部分的大体积C5-烷氧基取代基是不利的，因为它们直接指向细胞外前庭的水性环境。关键词：抗精神病药；抗精神病药行为研究，G蛋白偶联受体；吲哚衍生物多目标化合物精神分裂症。

更新日期：2019-07-20

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