Weil Annette, Moore Stephen E, Waite Nicola J, Randall Andrew, Gunthorpe Martin J
Neurology and GI-CEDD, GlaxoSmithKline, Harlow, Essex, CM19 5AW, UK.
Mol Pharmacol. 2005 Aug;68(2):518-27. doi: 10.1124/mol.105.012146. Epub 2005 May 23.
Members of the transient receptor potential (TRP) superfamily of ion channels have now been defined as molecular transducers capable of reproducing the spectrum of temperature sensation exhibited by mammals. Because of their pivotal role in sensory transduction, many of these channels represent good targets for drug discovery. With a view to gaining further insight into the functional and pharmacological properties of these channels, we have used the whole-cell patch-clamp technique to study the human cold-sensitive menthol receptor transient receptor potential melastatin 8 (TRPM8) and compared its behavior with that of its distant relative, the heat-sensitive capsaicin-gated transient receptor potential vanilloid 1 (TRPV1). It is remarkable to find that TRPM8, in addition to its behavior as an outwardly rectifying, nonselective cation channel, shares many functional and pharmacological properties with TRPV1. TRPM8 exhibits prominent time- and voltage-dependent behavior, a property that may underlie the conserved rectification or gating mechanisms exhibited by these channels. We also show that TRPM8 is modulated by ethanol but unlike TRPV1 is insensitive to extracellular acidification. There is also significant overlap in the antagonist pharmacology of these channels with many TRPV1 antagonists such as capsazepine, N-(4-tertiarybutylphenyl)-4-(3-chloropyridin-2-yl) tetrahydropyrazine-1(2H)-carboxamide (BCTC), (2R)-4-(3-chloro-2-pyridinyl)-2-methyl-N-[4-(trifluoromethyl)phenyl]-1-piperazinecarboxamide (CTPC), and N-(2-bromophenyl)-N'-{2-[ethyl(3-methylphenyl)amino]ethyl}-urea (SB-452533) exhibiting similar activity at TRPM8. Overall, the degree of pharmacological overlap between TRPV1 and TRPM8 has implications for the interpretation of studies conducted with these ligands to date and highlights a clear challenge for the design of selective TRP channel antagonists. Our finding that N-(3-methoxyphenyl)-4-chlorocinnamide (SB-366791), at least, represents an apparently selective antagonist for TRPV1 suggests that this goal is attainable.
瞬时受体电位（TRP）离子通道超家族的成员现已被定义为能够重现哺乳动物所表现出的温度感觉谱的分子换能器。由于它们在感觉转导中起关键作用，这些通道中的许多都代表了药物发现的良好靶点。为了进一步深入了解这些通道的功能和药理学特性，我们使用全细胞膜片钳技术研究了人类冷敏薄荷醇受体瞬时受体电位褪黑素8（TRPM8），并将其行为与其远亲、热敏辣椒素门控瞬时受体电位香草酸1（TRPV1）的行为进行了比较。值得注意的是，TRPM8除了作为外向整流、非选择性阳离子通道的行为外，还与TRPV1具有许多功能和药理学特性。TRPM8表现出显著的时间和电压依赖性行为，这一特性可能是这些通道所表现出的保守整流或门控机制的基础。我们还表明，TRPM8受乙醇调节，但与TRPV1不同，它对细胞外酸化不敏感。这些通道的拮抗剂药理学也有显著重叠，许多TRPV1拮抗剂，如辣椒素、N-（4-叔丁基苯基）-4-（3-氯吡啶-2-基）四氢吡嗪-1（2H）-甲酰胺（BCTC）、（2R）-4-（3-氯-2-吡啶基）-2-甲基-N-[4-（三氟甲基）苯基]-1-哌嗪甲酰胺（CTPC）和N-（2-溴苯基）-N'-{2-[乙基（3-甲基苯基）氨基]乙基}-脲（SB-452533）在TRPM8上表现出类似的活性。总体而言，TRPV1和TRPM8之间的药理学重叠程度对迄今为止使用这些配体进行的研究的解释有影响，并突出了设计选择性TRP通道拮抗剂的明显挑战。我们发现N-（3-甲氧基苯基）-4-氯肉桂酰胺（SB-366791）至少代表了一种对TRPV1明显选择性的拮抗剂，这表明这个目标是可以实现的。
