NEW PHARMACOLOGICAL TOOLS FOR ALPHA ADRENERGIC RECEPTORS

α 肾上腺素能受体的新药理学工具

• 批准号: 2431254
• 负责人: JOHN M WETZEL
• 金额: $ 37.22万
• 依托单位: SYNAPTIC PHARMACEUTICAL CORPORATION
• 依托单位国家: 美国
• 财政年份: 1994
• 资助国家: 美国
• 起止时间: 1994-09-15 至 1998-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2431254
• 关键词: affinity labeling; alpha adrenergic receptor; autoradiography; drug design /synthesis /production; radiotracer; receptor binding

Alpha 1 and alpha 2 adrenergic receptors serve numerous functions throughout the central and peripheral nervous systems and, as such, have served as useful targets for the development of drugs to treat of a number of disorders such as narcolepsy, intractable pain, hypertension, benign prostatic hyperplasia and glaucoma. Unfortunately, many alpha adrenergic drugs that have been developed have had significant side-effects which have limited their therapeutic usefulness. The recent identification of six alpha adrenergic receptor subtypes (alpha1a, alpha1b, alpha1d, alpha2a, alpha2b, alpha2c) may allow for the discovery of improved therapeutic alpha adrenergic agents with improved efficacy and fewer side-effects. The proposed research involves the design and synthesis of subtype- selective alpha adrenergic irreversible ligands, photoaffinity ligands and radioligands. These tool compounds will be characterized using cloned human, rat and dog alpha adrenergic receptors and used to study the distribution and functional relevance of alpha 1 and alpha 2 subtypes in intact tissues. In addition, these tool ligands will also be used in structure-function studies using mutated and chimeric receptors to study ligand-receptor interactions. These studies should provide valuable information which will aid the discovery of novel subtype-selective adrenergic drugs. PROPOSED COMMERCIAL APPLICATION: This research will lead to the development of novel, subtype-selective drugs which target alpha adrenergic receptors and may be useful for the treatment of diseases such as narcolepsy, intractable pain, hypertension, begin prostatic hyperplasia, urinary incontinence and glaucoma with fewer side-effects than existing therapeutic agents.

alpha 1和alpha 2肾上腺素能受体发挥了许多功能 在整个中央和周围神经系统中，因此 作为开发药物的有用目标 疾病，例如睡病，顽固性疼痛，高血压，良性 前列腺增生和青光眼。 不幸的是，许多α肾上腺素能 开发的药物具有重要的副作用 限制他们的治疗用途。 最近的六个识别 α肾上腺素能受体亚型（alpha1a，alpha1b，alpha1d，alpha2a， alpha2b，alpha2c）可能可以发现改善的治疗性α 肾上腺素能有提高功效和副作用较少的肾上腺素。 提出的研究涉及亚型的设计和合成 选择性α肾上腺功能不可逆的配体，光亲和配体和 放射线。 这些工具化合物将使用克隆来表征 人，大鼠和狗α肾上腺素能受体，用于研究 Alpha 1和Alpha 2亚型的分布和功能相关性 完整的组织。 此外，这些工具配体也将在 使用突变和嵌合受体进行研究的结构功能研究 配体 - 受体相互作用。 这些研究应提供有价值的 将有助于发现新型亚型选择性的信息 肾上腺素药。 拟议的商业应用：这项研究将导致 靶向α肾上腺素能的新型亚型选择性药物的开发 受体，可能对治疗诸如疾病的治疗有用 睡病，顽固性疼痛，高血压，开始前列腺增生， 尿失禁和青光眼的副作用少于现有 治疗剂。

项目成果

Synthesis and structure-activity relationship of fluoro analogues of 8-{2-[4-(4-methoxyphenyl)piperazin-1yl]ethyl}-8-azaspiro[4.5]decane-7,9-dione as selective alpha(1d)-adrenergic receptor antagonists.

选择性α(1d)- 8-{2-[4-(4-甲氧基苯基)哌嗪-1基]乙基}-8-氮杂螺[4.5]癸烷-7,9-二酮氟类似物的合成及构效关系

• DOI: 10.1021/jm0491391
• 发表时间: 2005
• 期刊: Journal of medicinal chemistry.
• 作者: Konkel,MichaelJ;Wetzel,JohnM;Cahir,Marie;Craig,DouglasA;Noble,StewartA;Gluchowski,Charles
• 通讯作者: Gluchowski,Charles