Mixed Kappa/Mu Opioids: Synthesis and Evaluation

混合 Kappa/Mu 阿片类药物：合成与评估

• 批准号: 6359306
• 负责人: John L Neumeyer
• 金额: $ 31.26万
• 依托单位: MCLEAN HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-09-01 至 2004-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6359306
• 关键词: analog; cocaine; drug abuse chemotherapy; drug addiction; drug design /synthesis /production; drug screening /evaluation; laboratory mouse; morphinans; narcotic antagonists; opioid receptor; pharmacokinetics; receptor binding; tissue /cell culture

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.

描述（由申请人提供）：这是一个新的R 01申请，继续 并扩大在合作协议（U-19）的支持下开始的研究， NIDA根据其可卡因成瘾创新研究战略计划 药物治疗（SPIRCAP）。κ阿片类药物可能作为功能性拮抗剂， 可卡因，我们已经发现，kappa阿片类药物与混合活性在两个kappa 和μ受体更有效地减少可卡因自我给药， 比高选择性的κ阿片类药物副作用更少。我们现在建议测试 μ阿片活性对于最佳抗可卡因是重要的假设 通过合成具有完整κ的阿片类药物的κ阿片激动剂的作用 激动剂活性和系统地改变在μ 受体的第二个目标是增加药理作用的持续时间， 因为κ阿片类药物通常作用时间很短第三个目标是 减少急性kappa阿片类药物后有时出现的毒性作用 局所得的新型混合κ/μ阿片类药物应具有 药效学和药代动力学特征显著优于kappa 阿片类药物目前可用。 基于我们的临床前发现，我们现在建议合成 环啡烷和新的N-烷基类似物; 10-酮基-吗啡喃衍生物; 6-氧杂-和 8-氧吗啡烷;吗啡烷和乙基酮环唑辛的氨基噻唑类似物 （EKC）。在每个系列中，大约有10种化合物， 合成它们的N-烷基取代基。将对每种化合物进行评估 用于对κ、μ和δ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。化合物与 将进一步评估κ受体的Ki值< 5 nM， 使用μ、κ和δ受体的激动剂/拮抗剂功效 [35 S] GTP γ S结合测定。新κ的抗伤害感受性质 将使用醋酸扭体试验和尾 闪烁测定[35 S] GTP γ S结合试验将给出体外 功效的测定和抗伤害感受试验将产生体内 功效的测定。这些研究的目标是获得化合物 它们是具有不同程度的激动剂和拮抗剂活性的κ激动剂 在μ受体上。这两种功效的测量将使我们能够开发 这些化合物的药理学特征可以让我们预测 化合物将有效减少可卡因自我给药。化合物 具有所需药理学特征的药物将在 姆克林医院酒精和药物滥用研究中心，但支持这些 本申请不要求进行研究。 Kappa阿片类药物合成将在酒精和药物滥用 姆克林医院研究中心，在约翰L。诺伊迈尔， 博士新化合物的体内和体外评价将由Jean M. Bidlack博士，在药理学和生理学系， 罗切斯特大学下，一个财团安排。