De Petrocellis Luciano, Moriello Aniello S
Endocannabinoid Research Group, Institute of Biomolecular Chemistry, CNR, Pozzuoli, Italy.
Recent Pat CNS Drug Discov. 2013 Dec;8(3):180-204. doi: 10.2174/1574889808666131209124012.
The transient receptor potential vanilloid-1 cat ion channel (TRPV1) is a nonspecific cation channel that can be activated by multiple endogenous stimuli and is expressed predominantly in sensory neurons, where it serves as a key nodal point in pain transmission pathways. In mammals, TRPV1 displays a wide tissue and cellular expression including both the peripheral and central nervous system, and in the latter it is now recognized to have a broader distribution and function. The pharmacological modulation of TRPV1 represents a strategy for the treatment of a variety of disease states, particularly those requiring chronic pain management. The validation of the TRPV1 channel as a therapeutic target for the control of pain and inflammatory conditions in a variety of diseases and injury states, has prompted the development of several TRPV1 agonists and antagonists that have entered clinical trials. Studies comparing the analgesic effects of TRPV1 antagonists with and without significant CNS penetration demonstrated that a dual (both peripheral and central) action is required to produce broad-spectrum analgesia. TRPV1 can be considered as a target for next generation analgesics. However, although a number of compounds are in clinical trials, the therapeutic utility of TRPV1 agonist and antagonists is yet to be validated unequivocally. This review summarizes current clinical trials and recent patents with small molecule TRPV1 agonists and antagonists with a focus on neurological conditions.
瞬时受体电位香草酸受体1阳离子通道（TRPV1）是一种非特异性阳离子通道，可被多种内源性刺激激活，主要表达于感觉神经元，在疼痛传导通路中起关键节点作用。在哺乳动物中，TRPV1在包括外周和中枢神经系统在内的广泛组织和细胞中均有表达，目前已知其在中枢神经系统中的分布和功能更为广泛。TRPV1的药理调节是治疗多种疾病状态的一种策略，尤其是那些需要慢性疼痛管理的疾病。TRPV1通道作为控制多种疾病和损伤状态下疼痛和炎症的治疗靶点得到验证后，促使了几种TRPV1激动剂和拮抗剂进入临床试验。比较具有和不具有显著中枢神经系统渗透作用的TRPV1拮抗剂镇痛效果的研究表明，需要外周和中枢双重作用才能产生广谱镇痛效果。TRPV1可被视为下一代镇痛药的靶点。然而，尽管有多种化合物正在进行临床试验，但TRPV1激动剂和拮抗剂的治疗效用尚未得到明确验证。本综述总结了目前关于小分子TRPV1激动剂和拮抗剂的临床试验及近期专利，重点关注神经系统疾病。
