Novel Imidazoline Compound As Antidiabetic Agent

作为抗糖尿病药的新型咪唑啉化合物

• 批准号: 8101682
• 负责人: LINCOLN Paul EDWARDS
• 金额: $ 42.23万
• 依托单位: LOMA LINDA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-08-01 至 2013-08-01
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8101682
• 关键词: Adipocytes; Adrenergic Receptor; Adverse effects; Affect; Agonist; American; Antidiabetic Drugs; Binding; Blood Pressure; Brain; Brain region; Cardiovascular system; Chronic stress; Clinical; Clinical Trials; Coupled; Development; Diabetes Mellitus; Dose; Drug Interactions; Environment; European; Faculty; Genes; Glucose; Goals; Health; Healthcare; Heart; Hyperglycemia; Hypertension; Hypotension; Imidazolines; Immune Sera; Immunoprecipitation; In Vitro; Insulin; Insulin Resistance; Insulin Signaling Pathway; Kidney Failure; Lead; Ligands; Link; Medicine; Metabolic; Metabolic syndrome; Microinjections; Minority; Muscle Cells; Neuropathy; Non-Insulin-Dependent Diabetes Mellitus; PC12 Cells; Pathway interactions; Patients; Periodontal Diseases; Peripheral; Pharmaceutical Preparations; Phosphorylation; Play; Proteins; Proto-Oncogene Proteins c-akt; Rattus; Receptor Activation; Reporting; Research; Research Personnel; Retinal Diseases; Reverse Transcriptase Polymerase Chain Reaction; Risk; Role; School Dentistry; Scourge; Shipping; Ships; Signal Pathway; Signal Transduction; Small Interfering RNA; Smooth Muscle Myocytes; Techniques; Testing; Therapeutic Uses; Training; Transfection; Twin Multiple Birth; Underrepresented Minority; United States; Western Blotting; blood pressure regulation; compliance behavior; diabetic; diabetic patient; glucose disposal; glucose uptake; graduate student; imidazoline receptors; improved; in vivo; insulin receptor substrate 1 protein; knock-down; lipid metabolism; member; moxonidine; novel; overexpression; phosphatidylcholine-specific phospholipase C; receptor; receptor coupling; response

DESCRIPTION (provided by applicant): Type 2 Diabetes and hypertension are major health care crises affecting over 18 and 70 million Americans respectively. To date, pharmacologic treatment of many type 2 diabetic patients require separate agents for treating hyperglycemia and hypertension. S43126, an Imidazoline compound, has the potential to treat both diabetes and hypertension simultaneously. Previous results have shown that Imidazoline compounds that are agonists at the I1 -imidazoline receptor act centrally to lower blood pressure and also play a role in the treatment of insulin resistance and diabetes. Some Imidazoline compounds also bind a-adrenergic receptors, however S43126 is a selective agonist to the I1 -imidazoline receptor. Our general hypothesis states that imidazoline compounds exert metabolic effects by activation of PC-PLC and stimulation of glucose uptake. This hypothesis will be tested by two specific aims. (1) Imidazoline receptors are coupled to PC-PLC pathways and blood pressure reduction in vivo and (2) Imidazoline receptor activation is coupled to an increased uptake of glucose via the PI3K dependent pathway. Results obtained from this proposal will not only lead to an understanding of how a single compound can act to positively impact both hypertension and hyperglycemia but also advance imidazoline research and stimulate the development of these agents for therapeutic use in the United States. Furthermore, this project provides an excellent training environment for undergraduate and graduate students including underrepresented minorities. PUBLIC HEALTH RELEVANCE: Type 2 diabetes affects millions of people worldwide leading to a worsening of periodontal disease, renal failure, cardiovascular problems, retinopathy and neuropathy. Many diabetics also need medications for hypertension, and compliance becomes an issue with multiple medications. Novel imidazoline compounds offer the possibility of treating diabetes and hypertension with a single medication, thereby improving compliance and ultimately patient health.

描述（由申请人提供）：2型糖尿病和高血压分别是影响超过1800万和7000万美国人的主要卫生保健危机。迄今为止，许多2型糖尿病患者的药物治疗需要单独的药物来治疗高血糖和高血压。S43126是一种咪唑啉化合物，具有同时治疗糖尿病和高血压的潜力。先前的研究结果表明，咪唑啉类化合物是I1 -咪唑啉受体的激动剂，对降低血压起主要作用，并在胰岛素抵抗和糖尿病的治疗中发挥作用。一些咪唑啉类化合物也能结合a-肾上腺素能受体，但S43126是一种选择性咪唑啉受体激动剂。我们的一般假设认为咪唑啉化合物通过激活PC-PLC和刺激葡萄糖摄取来发挥代谢作用。这一假设将由两个具体目标来检验。(1)咪唑啉受体在体内与PC-PLC通路和血压降低偶联；(2)咪唑啉受体激活通过PI3K依赖通路与葡萄糖摄取增加偶联。从该提案中获得的结果不仅将使人们了解单一化合物如何对高血压和高血糖产生积极影响，而且还将推进咪唑啉的研究，并刺激这些药物在美国的治疗用途的发展。此外，该项目为本科生和研究生提供了良好的培训环境，包括少数族裔。