Design And Synthesis Of Drugs Acting On Central And Peri

中枢及末梢药物的设计与合成

• 批准号: 7337509
• 负责人: Kenner C Rice
• 金额: --
• 依托单位: NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7337509
• 关键词: Design; Synthesis; Drugs; Acting; Central

The design, synthesize and evaluation of novel nonpeptide ligands has been continued to provide tools for study of the corticotropin releasing hormone (CRH) receptor system receptors, cocaine receptors [DA transporter proteins] and the opioid receptors. These studies are providing further insight into the pathogenesis of stress-related disorders and drug abuse, and potential treatments for these disorders. The CRH system consists of saturable, high-affinity CRH1 and CRH2 receptors and their endogenous ligands located in anatomically well-defined regions of the central nervous system (CNS) and periphery with the CRH1 receptor mediating many CRH effects in the brain. This hormone is involved in regulation of a number of normal functions and in the pathogenesis of a number of disorders of primary interest to NIDDK including the development of insulin resistance. Excessive chronic activation of the CRH system is involved in the pathogenesis of eating and gastrointestinal disorders and many other disorders including drug abuse. We have studied antalarmin, R121919 and MJL-1-109.2 (CRHR1 receptor antagonist) and found that these compounds suppress self administration of alcohol in alcohol dependent rats but not in nondependent rats. Our findings suggest that CRHR1 antagonists may have utility in preventing alcohol withdrawal stress related human relapse to alcohol drinking and are complimentary to our earlier finding that antalarmin suppresses stress induced relapse to compulsive food seeking in a rat model. Earlier, we introduced LWH63 as a sub nM affinity CRHR1 receptor ligand. We have now tritiated this compound to high specific activity as a potential nonpeptide primary ligand for CRHR1 receptors in order to eliminate problems inherent in the use of high specific activity peptide ligands. From the foregoing, it is clear that CRH1 antagonists such as antalarmin can be valuable research tools and potential medications. Many opportunities exist for exploitation of current and developing knowledge of the CRH system through the development of nonpeptide drugs that either mimic or antagonize the effects of CRH and the other endogenous ligands at their recognition sites. We plan to further exploit current and developing knowledge of the CRH, opioid and biogenic amine systems through the development of nonpeptide drugs that either mimic or antagonize the effects of drugs and endogenous ligands at their recognition sites.

新型非肽配体的设计、合成和评估不断为促肾上腺皮质激素释放激素（CRH）受体系统受体、可卡因受体[DA转运蛋白]和阿片受体的研究提供工具。这些研究进一步深入了解了压力相关疾病和药物滥用的发病机制，以及这些疾病的潜在治疗方法。 CRH 系统由可饱和、高亲和力的 CRH1 和 CRH2 受体及其内源性配体组成，这些配体位于中枢神经系统 (CNS) 和外周解剖学明确的区域，CRH1 受体介导大脑中的许多 CRH 效应。这种激素参与多种正常功能的调节以及 NIDDK 主要关注的多种疾病的发病机制，包括胰岛素抵抗的发展。 CRH 系统的过度慢性激活与饮食和胃肠道疾病以及包括药物滥用在内的许多其他疾病的发病机制有关。我们研究了antalarmin、R121919 和MJL-1-109.2（CRHR1 受体拮抗剂），发现这些化合物可以抑制酒精依赖大鼠的自我饮酒，但不能抑制非酒精依赖大鼠的自我饮酒。我们的研究结果表明，CRHR1 拮抗剂可能有助于预防与酒精戒断压力相关的人类饮酒复发，并且与我们之前的发现相补充，即安塔拉明在大鼠模型中抑制压力诱导的强迫性食物寻找复发。早些时候，我们引入了 LWH63 作为亚 nM 亲和力 CRHR1 受体配体。我们现在已经将该化合物氚化为高比活性，作为 CRHR1 受体的潜在非肽主要配体，以消除使用高比活性肽配体所固有的问题。综上所述，很明显 CRH1 拮抗剂（例如 antalarmin）可以成为有价值的研究工具和潜在的药物。通过开发模拟或拮抗 CRH 和其他内源配体在其识别位点的作用的非肽药物，存在许多利用 CRH 系统的当前和正在发展的知识的机会。我们计划通过开发模拟或拮抗药物和内源性配体在其识别位点的作用的非肽药物，进一步利用 CRH、阿片类药物和生物胺系统的当前和正在发展的知识。

项目成果

The molecular mechanism of chronic delta-opioid-mediated adenylyl cyclase superactivation in Chinese hamster ovary cells stably expressing the delta-opiod receptor: A cellular model for tolerance and withdrawal

稳定表达δ-阿片受体的中国仓鼠卵巢细胞慢性δ-阿片介导的腺苷酸环化酶超激活的分子机制：耐受和戒断的细胞模型

• 发表时间: 2024-09-14
• 作者: M. Rubenzik

A CRH1 antagonist into the amygdala of mice prevents defeat-induced defensive behavior.

小鼠杏仁核中的 CRH1 拮抗剂可防止失败引起的防御行为。

• 发表时间: 2004-12
• 影响因子: 5.2
• 作者: Robison, C L;Meyerhoff, J L;Saviolakis, G A;Chen, W K;Rice, K C;Lumley, L A
• 通讯作者: Lumley, L A

Assessment of SNC 80 and naltrindole within a conditioned taste aversion design.

在条件性味觉厌恶设计中评估 SNC 80 和纳曲吲哚。

• 发表时间: 2000-08
• 作者: Hutchinson, A C;Simpson, G R;Randall, J F;Zhang, X;Calderon, S N;Rice, K C;Riley, A L
• 通讯作者: Riley, A L

Opioid peptide receptor studies. 14. Stereochemistry determines agonist efficacy and intrinsic efficacy in the [(35)S]GTP-gamma-S functional binding assay.

阿片肽受体研究。

• 发表时间: 2001-01
• 作者: Xu, H;Hashimoto, A;Rice, K C;Jacobson, A E;Thomas, J B;Carroll, F I;Lai, J;Rothman, R B
• 通讯作者: Rothman, R B

Effect of N-alkyl and N-alkenyl substituents in noroxymorphindole, 17-substituted-6,7-dehydro-4,5alpha-epoxy-3,14-dihydroxy-6,7:2',3'-indolomorphinans, on opioid receptor affinity, selectivity, and efficacy.

去甲氧基吗吲哚、17-取代-6,7-脱氢-4,5α-环氧-3,14-二羟基-6,7:2,3-吲哚吗啡喃中N-烷基和N-烯基取代基对阿片受体的影响

• 发表时间: 2001-04-26
• 影响因子: 7.3
• 作者: McLamore, S;Ullrich, T;Rothman, R B;Xu, H;Dersch, C;Coop, A;Davis, P;Porreca, F;Jacobson, A E;Rice, K C
• 通讯作者: Rice, K C