μ-receptoragonist.ppt

* Chapter 4 Analgesics, antitussives and expectorants 4.1 Analgesics 疼痛：是由创伤和疾病等多种原因引发的症状，剧烈的疼痛可引起生理功能紊乱，甚至休克。 Classification of Painkiller: Narcotic Anangesics :作用于中枢神经系统，抑制痛觉神经从而消除或缓解疼痛，多用于剧痛（acute pain）。 Antipyretic analgesics:具有解热、镇痛、抗炎作用，用于钝痛(chronic pain)如牙痛或头痛。 Difference: different mechanism Opioid receptor for the former Arachidonic acid cyclooxygenase inhibitor of the latter Opioid receptors: discovered in 1973 with three subtypes μreceptor agonist: strong addiction κ receptor agonist, addiction δ receptor agonist Narcotic analgesics includes opioid alkaloid morphine, its synthetic analogues and endogenous substance such as enkephalin, endorphin and dynorphin. 4.1.1 Morphine and its analogues Opium是罂粟科植物罂粟的未成熟的蒴果被划破后流出的白色浆汁，干燥后呈棕黑色膏状物。The immature fruit of Opium contains alkaloids, triterpenoids and steroids. Morphine was seperated from Opium in 1805 and its chemical structure was identified in 1923. The total synthesis was finished in 1952. Molecular structure and activity of morphine 天然的吗啡呈左旋性，右旋体无活性 5个手性中心：5R, 6S,9R,13S,14R 5个环 ，A、B和C构成部分氢化的菲环，C和E构成部分氢化的异喹啉环 B/C呈顺式，C/D呈反式，C/E呈顺式 立体构像：三维的T Physiological activity：analgesia Side-effects: addiction, respiratory depression,Vomiting, constipation, euphoria 1. To simplify the chemical structure of morphine to develop synthetic morphine analogues and morphine antagonists. 2.To discover the mixed agonist-antagonist analgesics with small addiction. 3.To discover the efficient analgesics, such as the discovery of Etorphine 4.To discover the endogenous opioid-like analgesics such as enkephalin Modifications towards morphine Heroine Codeine Ethylmorphine Heterocodeine Oxycodone Hydromorphone Oxymorphone Hydrocodone N-β-phenylethylnormorphine N-CH3用其他烷基、链烯烃或芳烃修饰 活性为吗啡的4倍 Mixed agonist-antagonist Nalorphine μ-receptor partial agonist, very weak analgesic effect. Opioid antagonists and Antagonist analgesics Naloxone and naltrexone are μ-receptor antagonists, without exciting activity. Naloxone naltrexone 是研