TRPM8 has been implicated in nociception and pain and is currently regarded as an attractive target for the pharmacological treatment of neuropathic pain syndromes. A series of analogues of N,N′-dibenzyl tryptamine 1, a potent TRPM8 antagonist, was prepared and screened using a fluorescence-based in vitro assay based on menthol-evoked calcium influx in TRPM8 stably transfected HEK293 cells. The tryptophan derivative 14 was identified as a potent (IC₅₀ 0.2 ± 0.2 nM) and selective TRPM8 antagonist. In vivo, 14 showed significant target coverage in both an icilin-induced WDS (at 1–30 mg/kg s.c.) and oxaliplatin-induced cold allodynia (at 0.1–1 μg s.c.) mice models. Molecular modeling studies identified the putative binding mode of these antagonists, suggesting that they could influence an interaction network between the S1–4 transmembrane segments and the TRP domains of the channel subunits. The tryptophan moiety provides a new pharmacophoric scaffold for the design of highly potent modulators of TRPM8-mediated pain.

中文翻译：

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具有体内止痛活性的基于色氨酸的有效TRPM8拮抗剂的鉴定。

TRPM8与疼痛和疼痛有关，目前被认为是神经性疼痛综合征药物治疗的诱人靶标。制备了一系列有效的TRPM8拮抗剂N，N'-二苄基色胺1的一系列类似物，并基于基于薄荷醇的钙内流在TRPM8稳定转染的HEK293细胞中进行了基于荧光的体外测定，并进行了筛选。色氨酸衍生物14被鉴定为有效（IC ₅₀ 0.2±0.2 nM）和选择性TRPM8拮抗剂。体内14在icilin诱导的WDS（1–30 mg / kg sc）和奥沙利铂诱导的冷异常性疼痛（0.1–1μgsc）小鼠模型中均显示出显着的靶标覆盖率。分子模型研究确定了这些拮抗剂的假定结合模式，表明它们可能影响S1-4跨膜区段与通道亚基的TRP结构域之间的相互作用网络。色氨酸部分提供了一种新的药效学支架，用于设计TRPM8介导的疼痛的高效调节剂。