GASTROINTESTINAL EFFECTS OF DELTA AGONISTS

该项目将支持设计和引进高选择性的 作为镇痛剂的非肽δ阿片激动剂、预防药物 和治疗阿片依赖性，以及作为抗精神病药物。 的 δ激动剂的预期优点是缺乏便秘或其他 在完全镇痛剂量下的不良胃肠道作用。 新 具有良好镇痛性能的合成化合物将 通过三种途径在小鼠中进行快速、经济的评估 给药对胃排空，小肠转运， 和一个肠池（对盐的粘膜运输的影响的测量 和水）。 使用的给药途径为口服、系统给药、 注射（i. p.）和脑内注射（i. c. v.）。 这些研究将 特征剂量-反应和时间-反应效力评价， 生物利用度和药效学作用持续时间。 结果将 被化学家们用于进一步的分子设计。 选择 基于镇痛作用的化合物显示出特殊的前景， 小鼠的胃肠道特征，将进行确定性的 在大鼠中进行的三种给药途径的研究（p.o.，i.p.，i.c.v.） 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 δ阿片 确定并明确了这些终点的活动模式 药理学的目标。 将采用的技术是 正在进行中，并已证明在人类中的预测价值。

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.