Suh Young-Ger, Oh Uhtaek
College of Pharmacy, Seoul National University, Kwanak, Shinlim 9-dong, Seoul 151-742, Korea.
Curr Pharm Des. 2005;11(21):2687-98. doi: 10.2174/1381612054546789.
TRPV1 is a channel expressed highly in small sensory neurons. TRPV1 is a ligand-gated, cation channel that is activated by heat, acid and capsaicin, a principal ingredient in hot peppers. Because of its possible role as a polymodal molecular detector, TRPV1 is studied most extensively. In mice lacking TRPV1, thermal hyperalgesia induced by inflammation is reduced, suggesting a role for mediating inflammatory pain. Activity of TRPV1 is modulated by actions of various kinases such as protein kinase A and C. Furthermore, phosphorylation by Ca(2+)-calmodulin-dependent kinase II is required for its ligand binding. TRPV1 is activated by various endogenous lipids, such as anandamide, N-arachidonoyl-dopamine, and various metabolic products of lipoxygenases. 12-hydroperoxyeicosatetraenoic acid, an immediate metabolic product of 12-lipoxygenase, activates TRPV1 and shares 3-dimensional structural similarity with capsaicin. Because lipoxygenase products can activate TRPV1 in sensory neurons, upstream signals to lipoxygenase/TRPV1 pathway have been questioned. Indeed, bradykinin, a potent pain-causing substance, is now known to activate TRPV1 via lipoxygenase pathway. However, we cannot overlook the sensitizing effect of bradykinin via the phospholipase C or protein kinase C pathway. Interestingly, histamine, a pruritogenic substance, also appears to use the lipoxygenase/TRPV1 pathway in order to excite sensory neurons. Because of its role in the mediation of nociception, antagonists of TRPV1 are targeted for development of potential analgesics. In the present review, theoretical background of organic synthesis of SC0030, a potent antagonist of TRPV1 is presented.
瞬时受体电位香草酸亚型1（TRPV1）是一种在小感觉神经元中高度表达的通道。TRPV1是一种配体门控阳离子通道，可被热、酸和辣椒素（辣椒中的主要成分）激活。由于其作为多模式分子探测器的潜在作用，TRPV1得到了最广泛的研究。在缺乏TRPV1的小鼠中，炎症诱导的热痛觉过敏有所减轻，这表明它在介导炎性疼痛中发挥作用。TRPV1的活性受到多种激酶（如蛋白激酶A和C）作用的调节。此外，钙调蛋白依赖性激酶II的磷酸化是其配体结合所必需的。TRPV1可被多种内源性脂质激活，如花生四烯乙醇胺、N-花生四烯酰多巴胺以及脂氧合酶的各种代谢产物。12-氢过氧二十碳四烯酸是12-脂氧合酶的直接代谢产物，可激活TRPV1，且与辣椒素具有三维结构相似性。由于脂氧合酶产物可激活感觉神经元中的TRPV1，脂氧合酶/TRPV1途径的上游信号受到了质疑。事实上，缓激肽是一种强效致痛物质，现已知道它可通过脂氧合酶途径激活TRPV1。然而，我们不能忽视缓激肽通过磷脂酶C或蛋白激酶C途径产生的致敏作用。有趣的是，组胺是一种致痒物质，似乎也利用脂氧合酶/TRPV1途径来刺激感觉神经元。由于其在伤害感受介导中的作用，TRPV1拮抗剂成为了潜在镇痛药开发的靶点。在本综述中，介绍了TRPV1强效拮抗剂SC0030有机合成的理论背景。
