BCTC 是前列腺癌 (PCa) DU145 细胞中瞬时受体电位阳离子通道亚家族 M 成员 8 (TRPM8) 的有效特异性抑制剂 |MedChemExpress (MCE)

CAS：393514-24-4

品牌：MedChemExpress (MCE)

存储条件：Powder: -20°C, 3 years; 4°C, 2 years.In solvent: -80°C, 6 months; -20°C, 1 month.

生物活性：BCTC 是前列腺癌 (PCa) DU145 细胞中瞬时受体电位阳离子通道亚家族 M 成员 8 (TRPM8) 的有效特异性抑制剂。靶标：TRPM8 体外：BCTC 是 TRPM8 的强效特异性拮抗剂，对雄激素非依赖性 PCa DU145 细胞发挥抗肿瘤作用，以及抑制作用的机制。 BCTC 对 DU145 细胞发挥抗增殖作用，并通过 G0/G1 细胞周期停滞、迁移和侵袭抑制诱导肿瘤抑制。 BCTC 在 PCa DU145 细胞中表现出优异的抗肿瘤活性，因此有可能成为针对 PCa 的靶向治疗策略。 [1] 在体内：BCTC 是大鼠 VR1 的有效、选择性和口服生物利用度拮抗剂。 BCTC 不仅可以阻断辣椒素对大鼠 VR1 的激活，还可以阻断皮肤神经制剂中天然大鼠 VR1 的低 pH 值。因此，BCTC 为我们提供了一个机会来检验我们的假设，即抑制低 pH 诱导的 VR1 激活在慢性疼痛模型中赋予体内功效。本报告描述了 BCTC 在大鼠炎症、神经性疼痛和辣椒素引起的疼痛模型中的作用。 BCTC 在这些模型中的疗效和副作用概况分别与目前用于炎症和神经性疼痛临床治疗的非甾体类抗炎药和抗癫痫药进行了比较。 [2]

体外：BCTC (20-100 μM; 72 h) 对 DU145 细胞有高选择性的抗肿瘤活性[1]。 BCTC (20-100 μM; 48 h) 通过选择性的调节细胞周期调节蛋白亚群的表达水平来诱导细胞周期阻滞在G0/G1 期，且不引发细胞凋亡[1]。 BCTC (10 μM 和 100 μM; 48 h) 抑制细胞的迁移和侵袭[1]。 BCTC (3-300 nM) 可以通过抑制辣椒素 (300 nM) 诱导的大鼠脊髓切片中降钙素基因相关肽样免疫反应性 (CGRP-LI) (IC50=37.0 nM) 和 p 样物质免疫反应性 (SP-LI) (IC50=36.0 nM) 的释放，从而有效抑制大鼠脊髓 TRPV1 功能[3]。 MCE has not independently confirmed the accuracy of these methods. They are for reference only.

体内：BCTC (1-30 mg/kg; 口服给药; 单剂量) 可以通过靶向 VR1 来抑制 Sprague-Dawley 大鼠的炎症性和神经性的热痛觉和机械性痛觉过敏，具有镇痛作用[2]。 BCTC (10-100 mg/kg; 口服给药，一天2次连续4周) 可以改善糖尿病 ob/ob 小鼠的胰岛素抵抗和全身糖脂代谢，增加胰岛素的分泌[5]。 MCE has not independently confirmed the accuracy of these methods. They are for reference only. Animal Model: Capsaicin-induced Sprague-Dawley rats model[2] Dosage: 1 mg/kg, 3 mg/kg, 10 mg/kg, 30 mg/kg Administration: Oral gavage (p.o.), Single dose. Before capsaicin (HY-10448) treatment (30 μg; intraplantar injection; Single dose) Result: Inhibited capsaicin-mediated thermal hyperalgesia in a dose-dependent manner. Animal Model: Freund’s complete adjuvant (FCA) Sprague-Dawley rats model[2] Dosage: 1 mg/kg, 3 mg/kg, 10 mg/kg, 30 mg/kg Administration: Oral gavage (p.o.), Single dose. After 100 % FAC treatment (50 μL; intraplantar injection; Single dose) Result: Significantly reduced FAC-induced inflammation-related thermal pain and mechanical hyperalgesia, and extended the inhibitory effect of mechanical hyperalgesia to 6 h at high doses (10 mg/kg, 30 mg/kg). Animal Model: Partial sciatic nerve ligation Sprague-Dawley rats model[2] Dosage: 1 mg/kg, 3 mg/kg, 10 mg/kg, 30 mg/kg Administration: Oral gavage (p.o.), Single dose. After partial sciatic nerve ligation. Result: Reduced post-operative abnormal tactile pain and mechanical hyperalgesia in a dose-dependent manner. Animal Model: Particularly strong insulin resistance and hyperinsulinemia ob/ob mice model[5] Dosage: 10 mg/kg, 30 mg/kg, 100 mg/kg Administration: Oral gavage (p.o.); Twice daily for 4 weeks Result: Reduced plasma triglyceride and glucose area under the curve (AUC) level. Decreased calcitonin gene-related peptide (CGRP) levels in a dose-dependent manner.

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参考文献：

[1]. Liu T, et al. Anti-tumor activity of the TRPM8 inhibitor BCTC in prostate cancer DU145 cells. Oncol Lett. 2016 Jan;11(1):182-188.

[2]. Pomonis JD, et al. N-(4-Tertiarybutylphenyl)-4-(3-cholorphyridin-2-yl)tetrahydropyrazine -1(2H)-carbox-amide (BCTC), a novel, orally effective vanilloid receptor 1 antagonist with analgesic properties: II. in vivo characterization in rat models of inflammatory and neuropathic pain. J Pharmacol Exp Ther. 2003 Jul;306(1):387-93.

[3]. Kanai Y, et al. Involvement of an increased spinal TRPV1 sensitization through its up-regulation in mechanical allodynia of CCI rats. Neuropharmacology. 2005 Dec;49(7):977-84.

[4]. Nie C, et al. Study on chemical modification and analgesic activity of N-(4-tert-butylphenyl)-4-(3-chloropyridin-2-yl) piperazine-1-carboxamide. Eur J Med Chem. 2020 May 15;194:112236.

[5]. Tanaka H, et al. Enhanced insulin secretion and sensitization in diabetic mice on chronic treatment with a transient receptor potential vanilloid 1 antagonist. Life Sci. 2011 Mar 14;88(11-12):559-63.