反向药理学和基于传统药物的现代镇痛药的研发

Reverse Pharmacology and the R&D of Modern Analgesic Based on Traditional Medicines

摘要: 疼痛是许多急慢性疾患中皆可出现的症状，它是危及人类健康及防碍正常生活的主要问题之一。为了抗御疼痛，人类一直在孜孜不倦地寻求镇痛药物。目前临床上使用最多的镇痛药是以吗啡为代表的阿片生物碱类及其合成代用品(或称阿片类药物——opioids)和非甾体抗炎药(Nonsteroidal Antiinflammatory Drugs，NSAIDs)，它们都有较为严重的毒、副作用。一些致痛因子和炎性介质，如5-HT，ATP，BK，His，PGE2，SP等，其相应的受体阻断剂的应用对于镇痛虽有一定效应，但由于此等受体分布广泛，故选择性作用部位不强而且副作用也较多。因此关注的焦点主要集中在探索表达于中、小直径的初级感觉神经元的河豚毒素不敏感型(tetrodotoxin-resistant，TTX-R)钠通道和瞬时感受器电位香草酸受体1(transient potential vanilloid receptor1，TRPV1)。遗憾的是多年来在这方面并无突破性进展。以植物为本的各民族传统药物是当今国际药品市场的潜在丰富来源。遵循“反向药理学”的研究模式，形成先导物发现可践行的方法学，结合先进的科学技术和方法，从长期临床应用证实具有较显著镇痛功效和较少毒、副作用的传统药物中提取、分离多种单体化学成分，对其进行系统的药理研究，开发出化学结构和镇痛机理明确、安全性高的新型镇痛药物，将是镇痛药研发中具有较高效率的新途径。在我们的研究中，发现了两种对TTX-R钠通道和TRPV1均具有调制作用的民族药物——龙血竭和野木瓜。这两种药物在临床上都有较好的镇痛疗效，并且无成瘾性方面的记录。我们还确定了龙血竭调制TTX-R钠通道和TRPV1的药效物质基础是其化学成分剑叶龙血素A、剑叶龙血素B和龙血素B的组合。

Abstract: Pain is a major symptom in many medical conditions, and can significantly interfere with a person’s quality of life and general function. To relieve pain, people are unwearied to look for the analgesic drugs. Nowadays, the most popular analgesics in clinic practice are opioids and non-steroidal anti-inflammatory drugs (NSAIDs), both of which have some adverse reactions. Although the antagonists of some painful factor such as 5-HT, ATP, BK, His, PGE2 and SP receptors can relieve pain to some extent, they have some unpleasant side-effects and low selectivity for analgesic sites due to the wide distribution of them. Therefore, the focus of the research was concentrated on tetrodotoxin-resis- tant (TTX-R) sodium channel and transient potential vanilloid receptor 1(TRPV1) distributed in small-to-medium-sized primary sensory neurons. However, little breakthrough has been made for the past many years. The plentiful plant-derived national traditional medicine are potential resource of international pharmaceutical market nowadays. Based on the research framework of reverse pharmacology, combined with advanced science technique and methods, shaping into feasible methodology of discovering lead compounds, a new approach of developing analgesics is to ex- tract and separate various monomers from traditional medicine which have been confirmed significant efficacy and low side effect in clinic practice for a long period. The monomers will then be investigated systematically and developed into new analgesics with identified chemicial construction, clear-cut mechanism and high security. Our study discovered that two ethnodrugs, Dragon’s Blood Resin and Stauntonia chinensis DC., could interfere with pain messages and modulate TTX-R sodium and TPVR1 channels. They could produce excellent analgesic therapy in clinic without drug addiction. Moreover, the material basis for the modulation on TTX-R sodium channel and TPVR1 of Dragon’s Blood Resin was successfully validated to be the effective combination of cochinchinenin A, cochinchinenin B and loureirin B.