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物，来源于组胺拮抗剂。该原型（名为improgan）在直接注射到大脑后显示出以下特征：a)在热学和力学测试中表现出高度有效的、类似吗啡的抗痛觉作用；b)不损害运动协调或运动活动；e)不依赖于已知的组胺和阿片受体的机制；d)每日剂量缺乏耐受性；e)化学同源物之间独特的构效关系。这些药物的开发存在一些障碍：1)作用机制尚不清楚，2)高效同源物尚未发现，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），4)这些化合物在全身给药后不能穿透血脑屏障。在大鼠和小鼠实验中，我们将发现效价增强、毒副作用减少、穿透脑性能提高的新型益根镇痛同系物：目的1)合成并测试无H2和H3受体毒副作用、镇痛效价增强的新型益根类镇痛药。试点结果表明：开链；含呋喃的同系物会表现出这些性质。目的2)合成并测试脑穿透镇痛药。初步研究表明，发现这种化合物是可行的。目的3)确定这些新药对正在开发的两种新的放射配体结合试验的体外作用，以预测改善的镇痛。目的4)研究选定的新化合物在体内的活性：a)通过递质激动剂和拮抗剂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，将生产出具有吗啡功效和效力的新型、穿透大脑的非阿片类镇痛药。这些实验将有助于发现这类新型药物的作用机制，并导致新的药物治疗疼痛的发展。

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.