NON-OPIOID ANALGESICS DERIVED FROM IMPROGAN

从 IMPROGAN 中提取的非阿片类镇痛药

• 批准号: 6896773
• 负责人: LINDSAY HOUGH
• 金额: $ 28.09万
• 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/6896773
• 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）：最近发现了一种新的疼痛降低药物，这些药物是从组胺拮抗剂中得出的。该原型（命名为Impogan）在直接注入大脑后显示了以下特征：a）在热和机械测试中高效，类似吗啡样的抗热心敏感器，b）b）运动协调或运动活性的损害，e）与已知受体无关组合和阿片类药物的耐受性的机制，d）耐受性，d）与每日的耐受性相关性，以及独特的dossinty and dosing dossing dossing dossing dossing dossing dosings-dosings-dosings-dossing dossing dossing dossing dossing-dosing dossing dossing distosing dossing distosing distosing-dosings-e）。这些药物的发展中存在几种障碍：l）作用机理尚不清楚，2）尚未发现高功效的同类物，3）3）许多人具有H2或H3阻滞副作用（但通过这些受体产生镇痛），而4）化合物在系统性剂量后不会渗透到血液障碍物后。以下大鼠和小鼠的实验将发现新的Impogan的镇痛同源物具有增强的效力，副作用降低和改善的脑穿透特性：目标l）合成并测试缺乏H2和H3受体副作用的新型Improgan样止痛药，并且具有增强的肛门抗抗性剂。试点结果表明开放链；含有呋喃的同类物将显示这些特性。目标2）合成和测试脑穿透脑渗透不良状的镇痛药。 试点研究表明发现这种化合物的可行性。目的3）确定这些新药对开发的两种新的放射性结合测定法的体外作用，以预测造成反对的镇痛。 目标4）研究体内选定的新化合物的活性：a）通过用发射器激动剂和拮抗剂处理镇痛机制，b）评估其在几种不同的伤害感受测试和各种给药途径后评估其临床潜力。该项目是药物学家和药理学家之间的一项合作努力，将产生新的，脑部渗透的非阿片类镇痛药，并具有吗啡的功效和效力。这些实验将有助于发现这种新型药物类别的作用机理，并导致开发新的药物治疗疼痛。