NON-OPIOID ANALGESICS DERIVED FROM IMPROGAN

描述(申请人提供)：最近发现了一种从组胺拮抗剂中提取的新型止痛药。该原型(命名为Improgan)在直接注入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抗伤害性；b)运动协调或运动活动没有受损；e)其机制不依赖于组胺和阿片类药物的已知受体；d)缺乏对日常给药的耐受性；e)化学同系物之间存在独特的构效关系。这些药物的开发存在几个障碍：L)作用机制尚不清楚，2)高效同系物尚未被发现，3)许多具有H2或H3阻断的副作用(但不能通过这些受体产生止痛)，以及4)这些化合物在全身给药后不能穿透血脑屏障。在大鼠和小鼠体内的实验将发现新的异丙肾上腺素类止痛药，具有增强效力、减少副作用和改善脑穿透特性的特点：目的：L)合成和测试新的异丙肾上腺素类镇痛剂，它没有H2和H3受体的副作用，具有增强的镇痛效力。中试结果表明，开链呋喃同系物将表现出这些性质。目的2)合成并测试脑穿透即兴镇痛剂。初步研究表明，发现此类化合物是可行的。目的3)确定这些新药对两种新的放射性配基结合试验的体外作用，以预测不适当的镇痛。目的4)研究新化合物的体内活性：a)根据递质激动剂和拮抗剂的处理对其镇痛机制进行分类；b)在几种不同的伤害性试验和不同的给药途径中评估它们的临床潜力。该项目是药物化学家和药理学家之间的合作努力，将生产出具有吗啡效力和效力的新的、穿透大脑的非阿片类止痛药。这些实验将有助于发现这类新型药物的作用机理，并导致新的疼痛药物疗法的开发。

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.