GASTROINTESTINAL EFFECTS OF DELTA AGONISTS

该项目将支持设计和引入高度选择性的 非肽类阿片类激动剂作为止痛药和预防药物 和治疗阿片类药物依赖，以及作为止泻药。这个 Delta激动剂的预期优势是没有便秘或其他 止痛剂满剂量时会有不良胃肠道反应。新开 具有良好止痛性能的合成化合物将 通过三种途径在小鼠身上进行快速和经济的评估 给药对胃排空、小肠转运、 和一种肠道通透性(衡量盐分对粘膜运输的影响) 和水)。拟采用的给药途径是口服药、系统药 注射(Ip)和脑内注射(i.c.v)。这些研究将 效价的特征剂量反应和时间反应评价， 生物利用度和药效学作用时间。结果将 将被化学家用于进一步的分子设计。已选择 显示出非凡前景的化合物，基于止痛和 小鼠的胃肠道特征，将受到最终的 大鼠三种给药途径(P.O.，I.P.，I.C.V.)的研究 确定药物对局部收缩活动和推进的影响 在胃、小肠、盲肠和结肠。Delta阿片类药物 与这些端点的活动模式已建立并明确 提出了药理作用的目标。将采用的技术包括 正在进行中，并已被证明在人类中具有预测价值。

This project will support the design and introduction of highly selective nonpeptidic delta opioid agonist as analgesics, medicines for prevention and treatment of opiate dependence, and as antidiarrheal drugs. The anticipated advantage of delta agonist is lack of constipating or other adverse gastrointestinal effects at full analgesic doses. Newly synthesized compounds that exhibits favorable analgesic properties will be rapidly and economically evaluated in mice by three routes of administration for effects on gastric emptying, small intestinal transit, and one enteropooling (a measure of effects on mucosal transport of salt and water). The routes of administration to be employed are oral, system injection (i.p.) and intracerebral injection (i.c.v.). The studies will feature dose-response and time-response evaluations of potency, bioavailability, and pharmacodynamic duration of action. Results will be employed by the chemists in further molecular design. Selected compounds that show exceptional promise, based on analgesia and gastrointestinal profiles in mice, will be subjected to definitive studies in rats with three routes of administration (p.o., i.p.,i.c.v.) to determine drug effects on regional contractile activity and propulsion in the stomach, small intestine, cecum, and colon. The delta opioid patten of activity with these endpoints is established and clearcut pharmacological goals are presented. The techniques to be employed are ongoing and have proven predictive value in humans.