Biochemical Characterization of Opioid BInding Sites

阿片类药物结合位点的生化特征

• 批准号: 8253285
• 负责人: GAVRIL W PASTERNAK
• 金额: $ 56.19万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 1980
• 资助国家: 美国
• 起止时间: 1980-05-01 至 2014-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8253285
• 关键词: Absence of pain sensation; Address; Adverse effects; Analgesics; Animals; Behavior; Binding; Binding Sites; Biochemical; Brain; C-terminal; Cell Line; Clinical; Cloning; Complex; Development; Exons; Future; G-Protein-Coupled Receptors; Genes; Goals; Heterodimerization; Human; Investigation; Knockout Mice; Laboratories; Length; Literature; Methadone; Morphine; Mus; Opiates; Opioid; Opioid Analgesics; Opioid Receptor; Pain; Pain management; Pattern; Pharmaceutical Preparations; Pharmacology; Physical Dependence; Play; Protein Isoforms; Proteins; RNA Splicing; Rattus; Rewards; Role; Second Look Surgery; Series; Suggestion; Transgenic Mice; Transgenic Organisms; Transmembrane Domain; Variant; Work; analog; design; insight; interest; mu opioid receptors; neuroblastoma cell; novel; receptor; reconstitution; response

DESCRIPTION (provided by applicant): Opiates play a major role in the management of pain, but not without problems. Side-effects are often limiting and their increased availability has led to major societal problems with their abuse. Most opioids used clinically act through the mu receptor, a G-protein-coupled receptor encoded by the Oprm gene. The wide range of clinical responses to a number of mu opioids raised the question of multiple mu receptor subtypes, a concept that has been confirmed with cloning studies. The mu opioid receptor (MOR-1) has a wide range of splice variants, with similar splicing patterns in mice, rats and humans. There are two groups of variants. One is comprised of full length 7 transmembrane domain receptors with 3' splicing, differing only at the tip of the intracellular C-terminus. The other set involve truncated variants generated from 5' splicing of unclear significance. We recently generated a series of opioid analgesics with unique pharmacological profiles and found that they act through a novel receptor target involving a truncated MOR-1 variant. The objective of this proposal is to further understand these MOR-1 splice variants. The first aim focuses upon the target for IBNtxA and the six transmembrane domain variants that appear to be a component using a variety of approaches. The second looks at single transmembrane domain variants and their role in morphine analgesia and tolerance while the third explores the effects of 3' splicing in two full length variants. PUBLIC HEALTH RELEVANCE: Opiates remain the mainstay in the treatment of pain, but not without problems. Side-effects often interfere with their ability to control pain and there is increasing concern about their illicit use. A potent analgesic lacking side-effects and abuse potential would be of great value. Most opiates used today act through the mu opiate receptor. However, there now appear to be many forms of this receptor that may be useful in developing new classes of very potent analgesics lacking physical dependence, rewarding behavior and many of the side-effects seen with traditional drugs.

描述（由申请人提供）：阿片类药物在治疗疼痛方面发挥着重要作用，但并非没有问题。副作用往往是有限的，而且它们的可用性增加导致了滥用它们的重大社会问题。临床上使用的大多数阿片类药物通过 mu 受体发挥作用，mu 受体是一种由 Oprm 基因编码的 G 蛋白偶联受体。对多种 mu 阿片类药物的广泛临床反应提出了多种 mu 受体亚型的问题，这一概念已通过克隆研究得到证实。 mu阿片受体（MOR-1）具有广泛的剪接变体，在小鼠、大鼠和人类中具有相似的剪接模式。有两组变体。一种由具有 3' 剪接的全长 7 个跨膜结构域受体组成，仅在细胞内 C 末端的尖端有所不同。另一组涉及由意义不明的 5' 剪接产生的截短变体。我们最近开发了一系列具有独特药理学特征的阿片类镇痛药，并发现它们通过涉及截短的 MOR-1 变体的新型受体靶点发挥作用。该提案的目的是进一步了解这些 MOR-1 剪接变体。第一个目标侧重于 IBNtxA 的靶标和六种跨膜结构域变体，这些变体似乎是使用多种方法的组件。第二个研究着眼于单个跨膜结构域变体及其在吗啡镇痛和耐受性中的作用，而第三个研究则探讨了两个全长变体中 3' 剪接的影响。 公共卫生相关性：阿片类药物仍然是治疗疼痛的主要手段，但并非没有问题。 副作用常常会干扰它们控制疼痛的能力，并且人们越来越担心它们的非法使用。一种没有副作用和滥用可能性的强效镇痛药将具有很大的价值。 当今使用的大多数阿片类药物通过μ阿片类受体发挥作用。然而，现在似乎存在多种形式的这种受体，可用于开发新型非常有效的镇痛药，这些镇痛药缺乏身体依赖性、奖励行为和传统药物所见的许多副作用。