Mixed Kappa/Mu Opioids: Synthesis and Evaluation

描述(由申请人提供)：这是一个新的R01申请，继续 并延长在合作协议(U-19)的支持下开始的研究 NIDA的可卡因成瘾创新研究战略计划 药物疗法(SPIRCAP)。Kappa阿片类物质可作为功能性拮抗剂 可卡因，我们发现kappa阿片类药物在kappa和kappa两种情况下都有混合活性 Mu受体可更有效地减少可卡因的自我给药 副作用比高度选择性的kappa类阿片更少。我们现在建议测试一下 关于阿片类药物活性对最佳的可卡因反制很重要的假设 全kappa合成阿片类阿片激动剂的作用 激动剂活性并系统地改变MU的疗效程度 受体。第二个目标是增加药物作用的持续时间， 因为kappa类阿片类药物通常都是短效的。第三个目标是 减少急性kappa阿片类药物后的毒性作用 行政管理。由此产生的新型混合kappa/u阿片类药物应该具有 显著优于kappa的药效学和药代动力学 目前有阿片类药物。 根据我们的临床前研究结果，我们现在建议合成 环己烷和新的N-烷基类似物；10-酮-吗啉衍生物；6-氧杂-和 8-氧杂环戊烷；吗啡和乙基酮基环氮杂环唑的氨基噻唑类似物 (EKC)。在每个系列中，大约有10种化合物与 将合成它们的N-烷基取代基。将对每一种化合物进行评估 用于Kappa、Mu和Delta受体的体外亲和力和选择性 豚鼠脑膜和/或稳定转染的CHO细胞。含有以下成分的化合物 Kappa受体的KI值和5 nM将进一步评估 激动剂/拮抗剂在Mu、kappa和Delta受体上的疗效 [35S]GTP-GammaS结合试验。新型kappa的抗伤害作用 阿片类药物将在小鼠身上使用醋酸扭体试验和尾巴进行研究 闪光测定法。[35S]GTP-GammaS结合试验将在体外给出 疗效的测定和抗伤害试验将在体内产生一种 疗效的测定。这些研究的目标是获得化合物 它们是具有不同程度激动剂和拮抗剂活性的kappa激动剂 在Mu感受器。这两种有效性的测量将使我们能够开发出 这些化合物的药理学特征可以让我们预测 化合物将有效地减少可卡因的自我给药。化合物 将在猴子身上测试所需的药理特性 麦克莱恩医院酒精和药物滥用研究中心，但支持这些 本申请中不要求进行研究。 Kappa阿片类药物合成将在酒精和药物滥用处进行 McLean医院研究中心，在John L.Neumeyer的指导下， 新型化合物的体内和体外评价将由Jean进行 M·比德拉克，博士，哈佛大学药理学和生理学系 罗切斯特大学下，一家财团安排。

DESCRIPTION (provided by applicant): This is a new R01 application to continue and extend research begun with support from a cooperative agreement (U-19) with NIDA under its Strategic Program for Innovative Research on Cocaine Addiction Pharmacotherapy (SPIRCAP). Kappa opioids may act as functional antagonists of cocaine, and we have found that kappa opioids with mixed activity at both kappa and mu receptors decrease cocaine self-administration more effectively and with fewer side effects than highly selective kappa opioids. We now propose to test the hypothesis that mu opioid activity is important for optimal anti-cocaine effects of kappa opioid agonists by synthesizing opioids with full kappa agonist activity and systematically varying the degree of efficacy at the mu receptor. A second goal is to increase the duration of pharmacologic action, because kappa opioids are usually very short acting. A third goal is to decrease the toxic effects sometimes seen after acute kappa opioid administration. The resulting novel mixed kappa/mu opioids should have a significantly better pharmacodynamic and pharmacokinetic profile than kappa opioids currently available. On the basis of our preclinical findings, we now propose to synthesize cyclorphan and novel N-alkyl analogs; 10-keto-morphinan derivatives; 6-oxa- and 8-oxamorphinans; aminothiazole analogues of morphinans and ethylketocyclazocine (EKC). Within each series, approximately 10 compounds that vary with respect to their N-alkyl substituents will be synthesized. Each compound will be evaluated for in vitro affinity and selectivity for kappa, mu and delta receptors using guinea pig brain membranes and/or stably transfected CHO cells. Compounds with Ki values < 5 nM at kappa receptors will be further evaluated for agonist/antagonist efficacy at mu, kappa and delta receptors using [35S]GTPgammaS binding assays. Antinociceptive properties of novel kappa opioids will be studied in mice using an acetic-acid writhing test and a tail flick assay. The [35S]GTPgammaS binding assay will give an in vitro determination of efficacy and the antinociceptive tests will yield an in vivo determination of efficacy. The goal of these studies is to obtain compounds that are kappa agonists with varying degrees of agonist and antagonist activity at the mu receptor. These two measurements of efficacy will allow us to develop pharmacological profiles of the compounds that may allow us to predict which compounds will be effective in reducing cocaine self-administration. Compounds with the desired pharmacological profiles will be tested in monkeys at the McLean Hospital Alcohol and Drug Abuse Research Center, but support for these studies is not requested in this application. Kappa opioid synthesis will be carried out at the Alcohol and Drug Abuse Research Center, McLean Hospital, under the direction of John L. Neumeyer, Ph.D. Novel compound in vivo and in vitro evaluations will be conducted by Jean M. Bidlack, Ph.D., in the Department of Pharmacology and Physiology at the University of Rochester under, a consortium arrangement.