Novel Imidazoline Compound As Antidiabetic Agent

描述（由申请人提供）：2型糖尿病和高血压是主要的卫生保健危机，分别影响超过1800万和7000万美国人。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症和高血压。S43126是一种咪唑啉类化合物，具有同时治疗糖尿病和高血压的潜力。先前的结果表明，作为I1 -咪唑啉受体激动剂的咪唑啉化合物在中枢作用以降低血压，并且还在胰岛素抗性和糖尿病的治疗中起作用。一些咪唑啉化合物也结合α-肾上腺素能受体，但S43126是I1 -咪唑啉受体的选择性激动剂。我们的一般假设表明，咪唑啉化合物通过激活PC-PLC和刺激葡萄糖摄取发挥代谢作用。这一假设将通过两个具体目标进行检验。(1)咪唑啉受体与体内PC-PLC途径和血压降低偶联，以及（2）咪唑啉受体活化与通过PI 3 K依赖性途径增加的葡萄糖摄取偶联。从这一提案中获得的结果不仅将有助于了解单一化合物如何对高血压和高血糖产生积极影响，而且还将促进咪唑啉研究，并刺激这些药物在美国的治疗用途的开发。此外，该项目为本科生和研究生，包括代表性不足的少数民族提供了一个良好的培训环境。 公共卫生相关性：2型糖尿病影响全世界数百万人，导致牙周病、肾衰竭、心血管问题、视网膜病和神经病变的恶化。许多糖尿病患者也需要高血压药物，并且依从性成为多种药物的问题。新型咪唑啉化合物提供了用单一药物治疗糖尿病和高血压的可能性，从而改善依从性并最终改善患者健康。

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.