Elucidation of the molecular requirements of the low affinity 'state' of the beta1-adrenoceptor

阐明β1-肾上腺素受体低亲和力“状态”的分子要求

• 批准号: nhmrc : 351569
• 负责人: A/Pr Peter Molenaar
• 金额: $ 35.71万
• 依托单位: The University of Queensland
• 依托单位国家: 澳大利亚
• 项目类别: NHMRC Project Grants
• 财政年份: 2005
• 资助国家: 澳大利亚
• 起止时间: 2005-01-01 至 2007-12-31
• 项目状态: 已结题
• 来源: https://researchdata.edu.au/elucidation-molecular-requirements-beta1-adrenoceptor/76115
• 关键词: Elucidation; molecular; requirements; low; affinity

Beta-blockers are used for the management of cardiovascular diseases including heart failure, ischaemic heart disease and high blood pressure. Beta-blockers mostly work by blocking the effects of a naturally occuring chemical called noradrenaline. Beta-blockers can be used to prevent noradrenaline induced increases in the rate and force of human heart contraction. We have discovered that one group of beta-blockers exemplified by CGP 12177 has the remarkable property of not only being able to block beta-receptors but they can also stimulate them at higher concentrations. Thus low concentrations block the effects of noradrenaline, but higher concentrations stimulate the receptor. More puzzling is that the stimulant effects of this group of beta-blockers cannot be easily blocked. To explain this we hypothesize that human beta-receptors can exist in two different 'states'. One 'state' can be stimulated by noradrenaline and blocked by low concentrations of beta-blockers such as propranolol and CGP 12177. Another 'state' of the same receptor is resistant to blockade by beta-blockers such as propranolol but can be stimulated by beta-blockers such as CGP 12177. This project seeks to investigate the molecular basis of the beta-adrenoceptor that is responsible for stimulant effects of beta-blockers. Specifically it explores the components of the beta-adrenoceptor that are critically and uniquely important for interacting with the stimulant beta-blockers. This project is an important increment in our laboratories research program to increase our understanding of the effects of beta-blockers. Our long term goal is to be able to develop beta-blockers that can block both states of the beta-adrenoceptor to provide a more effective block of the receptor and in particular for the improved management of heart failure.

β受体阻滞剂用于治疗心血管疾病，包括心力衰竭、缺血性心脏病和高血压。β受体阻滞剂主要通过阻断一种叫做去甲肾上腺素的天然化学物质的作用来起作用。β-受体阻滞剂可用于防止去甲肾上腺素诱导的人心脏收缩速率和力量的增加。我们已经发现，以CGP 12177为例的一组β受体阻滞剂具有显著的特性，不仅能够阻断β受体，而且还可以在更高的浓度下刺激它们。因此，低浓度阻断去甲肾上腺素的作用，但高浓度刺激受体。更令人困惑的是，这组β受体阻滞剂的兴奋作用并不容易被阻断。为了解释这一点，我们假设人类β受体可以以两种不同的“状态”存在。一种“状态”可以被去甲肾上腺素刺激，并被低浓度的β受体阻滞剂如普萘洛尔和CGP 12177阻断。同一受体的另一种“状态”是对β受体阻滞剂如普萘洛尔的阻断有抵抗力，但可以被β受体阻滞剂如CGP 12177刺激。该项目旨在研究β受体的分子基础，β受体是负责β受体阻滞剂的兴奋作用。具体来说，它探讨了β-肾上腺素受体的组成部分，这是至关重要的和独特的重要性，与兴奋剂β-受体阻滞剂。该项目是我们实验室研究计划的重要增量，以增加我们对β受体阻滞剂作用的理解。我们的长期目标是能够开发出能够阻断β-肾上腺素受体两种状态的β-受体阻滞剂，以提供更有效的受体阻断，特别是用于改善心力衰竭的管理。