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首页> 外文期刊>European Journal of Medicinal Chemistry: Chimie Therapeutique >A solid-phase combinatorial approach for indoloquinolizidine-peptides with high affinity at D-1 and D-2 dopamine receptors
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A solid-phase combinatorial approach for indoloquinolizidine-peptides with high affinity at D-1 and D-2 dopamine receptors

机译:对D-1和D-2多巴胺受体具有高亲和力的吲哚并喹唑烷肽的固相组合方法

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摘要

Ligands acting at multiple dopamine receptors hold potential as therapeutic agents for a number of neurodegenerative disorders. Specifically, compounds able to bind at D1R and D2R with high affinity could restore the effects of dopamine depletion and enhance motor activation on degenerated nigrostriatal dopaminergic systems. We have directed our research towards the synthesis and characterisation of heterocycle-peptide hybrids based on the indolo[2,3-a]quinolizidine core. This privileged structure is a water-soluble and synthetically accessible scaffold with affinity for diverse GPCRs. Herein we have prepared a solid-phase combinatorial library of 80 indoloquinolizidine-peptides to identify compounds with enhanced binding affinity at D2R, a receptor that is crucial to re-establish activity on dopamine-depleted degenerated GABAergic neurons. We applied computational tools and high-throughput screening assays to identify 9a{1,3,3} as a ligand for dopamine receptors with nanomolar affinity and agonist activity at D2R. Our results validate the application of indoloquinolizidine-peptide combinatorial libraries to fine-tune the pharmacological profiles of multiple ligands at D-1 and D-2 dopamine receptors. (C) 2015 Elsevier Masson SAS. All rights reserved.
机译:作用于多个多巴胺受体的配体具有作为许多神经退行性疾病的治疗剂的潜力。具体而言,能够在D1R和D2R处以高亲和力结合的化合物可以恢复多巴胺消耗的影响,并增强变性黑质纹状体多巴胺能系统的运动活化。我们已经将研究方向转向了基于吲哚[2,3-a]喹啉嗪核的杂环-肽杂化物的合成和表征。这种特权结构是对多种GPCR具有亲和力的水溶性和可合成获得的支架。本文中,我们制备了80种吲哚并喹喔啉-肽的固相组合文库,以鉴定对D2R具有增强结合亲和力的化合物,该受体对于在多巴胺耗尽的退化GABA能神经元上重建活性至关重要。我们应用了计算工具和高通量筛选分析方法,以鉴定9a {1,3,3}为多巴胺受体的配体,该受体在D2R具有纳摩尔摩尔亲和力和激动剂活性。我们的结果验证了吲哚喹唑啉-肽组合文库在微调D-1和D-2多巴胺受体上多个配体的药理学特征方面的应用。 (C)2015 Elsevier Masson SAS。版权所有。

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