NON-OPIOID ANALGESICS DERIVED FROM IMPROGAN

描述（由申请人提供）：最近发现了一类新的止痛药，来源于组胺拮抗剂。原型（命名为improgan）在直接注射到脑中后显示出以下特征：a）在热和机械测试中高度有效的吗啡样抗伤害感受，B）不损害运动协调或自发活动，e）不依赖于已知的组胺和阿片类受体的机制，d）缺乏对每日剂量的耐受性，以及e）化学同系物之间独特的结构-活性关系。在这些药物的开发中存在几个障碍：1）作用机制未知，2）尚未发现高效同源物，3）许多具有H2或H3阻断副作用（但不通过这些受体产生镇痛作用），以及4）在全身给药后化合物不穿透血脑屏障。以下在大鼠和小鼠中的实验将发现具有增强的效力、降低的副作用和改善的脑穿透性质的新的异丙根镇痛剂同系物：目的1）合成和测试新的异丙根样镇痛剂，其没有H2和H3受体副作用，并且具有增强的镇痛效力。试验结果表明，开链;含呋喃同系物将显示这些属性。目的2）合成并测试具有脑穿透性的类阿片镇痛药。 初步研究显示了发现此类化合物的可行性。目的3）用两种新的放射性配体结合法测定这些新药的体外镇痛作用。 目的4）研究所选新化合物的体内活性：a）通过用递质激动剂和拮抗剂治疗来分类它们的镇痛机制，和B）评估它们在几种不同的伤害感受性试验中和在各种给药途径后的临床潜力。该项目是药物化学家和药理学家之间的合作努力，将产生新的，脑渗透性，非阿片类镇痛剂，具有吗啡的功效和效力。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发展。

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.