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首页> 外文期刊>Journal of Medicinal Chemistry >Tryptamine-Based Derivatives as Transient Receptor Potential Melastatin Type 8 (TRPM8) Channel Modulators
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Tryptamine-Based Derivatives as Transient Receptor Potential Melastatin Type 8 (TRPM8) Channel Modulators

机译：基于色胺的衍生物作为瞬态受体潜在Melastatin 8型（TRPM8）通道调节剂

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摘要

Pharmacological modulation of the transient receptor potential melastatin type 8 (TRPM8) is currently under investigation as a new approach for the treatment of pain and other diseases. In this study, a series of N-substituted tryptamines was prepared to explore the structural requirements determining TRPM8 modulation. Using a fluorescence based screening assay, we identified two compounds acting as an activator (2-(1H-indol-3-yl)-N-(4-phenoxybenzyl)ethanamine, 21) or an inhibitor (N,N-dibenzyl-2-(1H-indol-3-yl)ethanamine, 12) of calcium influx in HEK293 cells. In patch-clamp recordings, compound 21 displayed a significantly higher potency (EC50 = 40 +/- 4 mu M) and a similar efficacy when compared to menthol; by contrast, compound 12 produced a concentration-dependent inhibition of menthol-induced TRPM8 currents (IC50 = 367 +/- 24 nM). Molecular modeling studies using a homology model of a single rat TRPM8 subunit identified a putative binding site located between the VSD and the TRP box, disclosing differences in the binding modes for the agonist and the antagonist.
机译：目前正在研究8型瞬时受体电位褪黑素（TRPM8）的药理学调节，作为治疗疼痛和其他疾病的新方法。在这项研究中，准备了一系列的N-取代的色胺，以探索确定TRPM8调节的结构要求。使用基于荧光的筛选测定法，我们确定了两种激活剂（2-（1H-吲哚-3-基）-N-（4-苯氧基苄基）乙胺，21）或抑制剂（N，N-二苄基-2） -（1H-吲哚-3-基）乙胺，12）的钙流入HEK293细胞。在膜片钳记录中，与薄荷醇相比，化合物21的效价显着更高（EC50 = 40 +/- 4μM），且功效相似。相比之下，化合物12对薄荷醇诱导的TRPM8电流产生浓度依赖性抑制（IC50 = 367 +/- 24 nM）。使用单个大鼠TRPM8亚基的同源性模型进行的分子建模研究确定了位于VSD和TRP盒之间的推定结合位点，从而揭示了激动剂和拮抗剂的结合方式不同。

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