NON-OPIOID ANALGESICS DERIVED FROM IMPROGAN

从 IMPROGAN 中提取的非阿片类镇痛药

• 批准号: 6579298
• 负责人: LINDSAY HOUGH
• 金额: $ 30.99万
• 依托单位: ALBANY MEDICAL COLLEGE
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-07-01 至 2007-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6579298
• 关键词: analgesics; autoradiography; blood brain barrier; brain metabolism; cimetidine; drug administration routes; drug adverse effect; drug design /synthesis /production; drug metabolism; drug screening /evaluation; histamine receptor; laboratory mouse; laboratory rat; nociceptors; pain; pharmacokinetics; radiotracer

DESCRIPTION (provided by applicant): A new class of pain-relieving drugs, derived from histamine antagonists, has recently been discovered. The prototype (named improgan) shows the following characteristics after direct injection into the brain: a) highly effective, morphine-like antinociception on thermal and mechanical tests, b) no impairment of motor coordination or locomotor activity, e) mechanism that is independent of known receptors for histamine and opioids, d) lack of tolerance with daily dosing, and e) unique structure-activity relationships among chemical congeners. Several impediments exist in the development of these agents: l) the mechanism of action is unknown, 2) high-potency congeners have not been discovered, 3) many have H2 or H3-blocking side effects (but do not produce analgesia through these receptors), and 4) the compounds do not penetrate the blood brain barrier after systemic dosing. The experiments below in rats and mice will discover new analgesic congeners of improgan with enhanced potency, reduced side effects and improved brain-penetrating properties: Aim l) Synthesize and test new improgan-like analgesics which lack H2 and H3 receptor side effects, and possess enhanced analgesic potency. Pilot results indicate that open chain; furan-containing congeners will show these properties. Aim 2) Synthesize and test brain-penetrating improgan-like analgesics. Pilot studies show the feasibility of discovering such compounds. Aim 3) Determine the in vitro actions of these new drugs on two new radioligand binding assays being developed to predict improgan analgesia. Aim 4) Study the activity of selected new compounds in vivo: a) classify their analgesic mechanism by treatments with transmitter agonists and antagonists, and b) assess their clinical potential in several different nociceptive tests and after various routes of administration. This project, which is a collaborative effort between medicinal chemists and pharmacologists, will produce new, brain-penetrating, non-opioid analgesics with the efficacy and potency of morphine. These experiments will help to discover the mechanism of action of this novel class of agents, and lead to the development of new pharmacotherapies for pain.

描述（由申请人提供）：最近发现了一种源自组胺拮抗剂的新型止痛药物。原型（名为improgan）在直接注射到大脑后显示出以下特征：a）在热和机械测试中具有高效的吗啡样镇痛作用，b）不会损害运动协调或运动活动，e）独立于已知的组胺和阿片类药物受体，d) 每日给药缺乏耐受性，e) 化学同源物之间独特的结构-活性关系。这些药物的开发存在几个障碍：l) 作用机制未知，2) 尚未发现高效同源物，3) 许多药物具有 H2 或 H3 阻断副作用（但不会通过这些受体产生镇痛作用） )，4) 全身给药后，化合物不会穿透血脑屏障。以下在大鼠和小鼠中的实验将发现新的 improgan 镇痛同系物，其具有增强的效力、减少的副作用和改善的脑穿透特性： 目标 l) 合成和测试新的 improgan 类镇痛剂，其没有 H2 和 H3 受体副作用，并具有增强镇痛效力。试点结果表明开放链；含呋喃同系物将显示出这些特性。目标 2) 合成并测试脑部穿透性类improgan镇痛药。 试点研究表明发现此类化合物的可行性。目标 3) 确定这些新药对两种新的放射性配体结合测定的体外作用，这些测定正在开发用于预测 improgan 镇痛作用。 目标 4) 研究所选新化合物的体内活性：a) 通过递质激动剂和拮抗剂治疗对其镇痛机制进行分类，b) 在几种不同的伤害性测试中以及在各种给药途径后评估其临床潜力。该项目是药物化学家和药理学家之间的合作项目，将生产具有吗啡功效和效力的新型脑穿透性非阿片类镇痛药。这些实验将有助于发现这类新型药物的作用机制，并导致新的疼痛药物疗法的开发。