Characterization of SB-705498, a potent and selective vanilloid receptor-1 (VR1/TRPV1) antagonist that inhibits the capsaicin-, acid-, and heat- mediated activation of the receptor
Characterization of SB-705498, a potent and selective vanilloid receptor-1 (VR1/TRPV1) antagonist that inhibits the capsaicin-, acid-, and heat- mediated activation of the receptor
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DOI：
10.1124/jpet.106.116657
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发表时间：
2007-06-01
影响因子：
3.5
通讯作者：
Davis, John B.
中科院分区：
文献类型：
--
作者：
Gunthorpe, Martin J.;Hannan, Sara Luis;Davis, John B.
香草素受体-1 （TRPV1）是一种非选择性阳离子通道，主要由感觉神经元表达，在辣椒素、酸和热等有害疼痛刺激的检测中起关键作用。TRPV1拮抗剂可能是治疗一系列疾病的新型治疗药物，包括慢性疼痛、偏头痛和胃肠道疾病。本文描述了一种新型TRPV1拮抗剂N-（2-溴苯基）-N'- [(（R)-1-（5-三氟甲基-2-吡啶基）吡咯烷-3-基）]尿素（nb -705498）的体外药理学研究。N-（2-溴苯基）-N'-{2-[乙基（3-甲基苯基）氨基]乙基}尿素（nb -452533）已进入临床试验。使用基于Ca2+的荧光成像板读取器（FLIPR）测定，SB-705498被证明是辣椒素介导的人类TRPV1受体（pK(i) = 7.6）激活的有效竞争拮抗剂，在大鼠（pK(i) = 7.5）和豚鼠（pK(i) = 7.3）同源物中具有活性。全细胞膜片钳电生理学用于证实和扩展这些发现，证明SB-705498可以有效抑制可能与TRPV1在体内的病理生理作用相关的多种受体激活模式：SB-705498可以快速和可逆地抑制辣椒素(IC50 = 3 nM)-，酸(pH 5.3)-或热（50℃；IC50 = 6 nM）-介导的人类TRPV1激活（在-70 mV）。有趣的是，SB-705498也表现出一定程度的电压依赖性，这表明在负电位下拮抗剂作用的有效增强，例如在体内神经元中可能遇到的那些电位。SB-705498的选择性是通过广泛的受体分析和其他细胞分析来确定的，其中它对广泛的离子通道，受体和酶显示很少或没有活性。因此，SB-705498代表了一种有效的、选择性的多模态TRPV1拮抗剂，其药理学特征有助于将其定义为适合临床开发的候选药物。
Vanilloid receptor-1 (TRPV1) is a nonselective cation channel, predominantly expressed by sensory neurons, which plays a key role in the detection of noxious painful stimuli such as capsaicin, acid, and heat. TRPV1 antagonists may represent novel therapeutic agents for the treatment of a range of conditions including chronic pain, migraine, and gastrointestinal disorders. Here we describe the in vitro pharmacology of N-(2-bromophenyl)- N'-[((R)-1-(5-trifluoromethyl-2-pyridyl)pyrrolidin-3- yl)] urea (SB-705498), a novel TRPV1 antagonist identified by lead optimization of N-(2-bromophenyl)-N'-{2-[ethyl(3-methylphenyl) amino] ethyl} urea (SB-452533), which has now entered clinical trials. Using a Ca2+-based fluorometric imaging plate reader (FLIPR) assay, SB-705498 was shown to be a potent competitive antagonist of the capsaicin-mediated activation of the human TRPV1 receptor (pK(i) = 7.6) with activity at rat (pK(i) = 7.5) and guinea pig (pK(i) = 7.3) orthologs. Whole-cell patch-clamp electrophysiology was used to confirm and extend these findings, demonstrating that SB-705498 can potently inhibit the multiple modes of receptor activation that may be relevant to the pathophysiological role of TRPV1 in vivo: SB-705498 caused rapid and reversible inhibition of the capsaicin (IC50 = 3 nM)-, acid (pH 5.3)-, or heat (50 degrees C; IC50 = 6 nM)- mediated activation of human TRPV1 (at - 70 mV). Interestingly, SB-705498 also showed a degree of voltage dependence, suggesting an effective enhancement of antagonist action at negative potentials such as those that might be encountered in neurons in vivo. The selectivity of SB-705498 was defined by broad receptor profiling and other cellular assays in which it showed little or no activity versus a wide range of ion channels, receptors, and enzymes. SB-705498 therefore represents a potent and selective multimodal TRPV1 antagonist, a pharmacological profile that has contributed to its definition as a suitable drug candidate for clinical development.