SYNTHESIS & STUDY OF HISTAMINE H2 RECEPTOR ANTAGONISTS

合成

• 批准号: 3438512
• 负责人: WILLIAM N SETZER
• 金额: $ 7.08万
• 依托单位: UNIVERSITY OF ALABAMA IN HUNTSVILLE
• 依托单位国家: 美国
• 财政年份: 1986
• 资助国家: 美国
• 起止时间: 1986-09-01 至 1989-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3438512
• 关键词: X ray crystallography; antiarrhythmic agent; antihistamines; chemical binding; conformation; dosage; drug design /synthesis /production; drug interactions; drug metabolism; gastric acid; gastric juice inhibitor; gastric mucosa; gastrointestinal pharmacology; heart pharmacology; myocardium; smooth muscle; spectrometry

Our purpose is to more fully understand the geometrical requirements of the histamine H2-receptor antagonists and the H2-receptor site. Specifically, syntheses of macrocyclic analogues of H2-receptor antagonists would be pursued. Such compounds would be locked into cis folded conformations and would provide insight into the nature of the interaction of antagonists with the H2-receptor site as assessed from biological data. The efficacy of these compounds as H2-receptor antagonists would be ascertained by pharmacologic protocols involving H2-specific tissues such as gastric mucosa, guinea pig right atrium, and rat uterus. Relative binding affinities (pA2) will be calculated from dose-response curves exhibiting competitive antagonism of histamine H2 sites by the synthesized compounds. Conformational analyses of these macrocyclic compounds would be studied by the use of molecular mechanics and molecular orbital techniques as well as spectroscopic and crystallographic methods. The pharmacological actions of histamine are considered to be mediated by at least two distinct classes of receptor, designated H1 and H2, distinguished by the action of specific histamine antagonists that selectively block histamine responses. Histamine evidently plays an important role on the gastric mucosa, smooth muscle, myocardium, adrenal medulla, and certain neural processes, and may involve cyclic AMP as a second messenger in these pharmacological actions. Histamine H2-receptor antagonists are widely used as effective inhibitors of gastric acid secretion in the treatment of duodenal ulcers and related conditions. Histamine receptors are also important in controlling heart rate. It appears as if H2 receptors are responsible for mediating histamine-induced idioventricular tachyarrhythmia. This may have important implications for the treatment of ventricular arrhythmia caused by histamine release. At present, the geometrical requirements of histamine H2-receptor antagonists are ambiguous. Neither the binding site geometry nor the requirements for efficient absorption of the antagonists are understood. Macrocyclic analogues of histamine H2-receptor antagonists would be useful in understanding the nature of interaction of antagonists with H2-receptor sites, and would provide additional information as to the geometrical and conformational requirements of these drugs. Apparent conformation-relative binding affinity relationships should provide insight for further histamine H2-receptor investigations.

我们的目的是更充分了解 组胺H2受体拮抗剂和H2受体位点。 具体来说， H2受体拮抗剂的大环类似物的合成将是 追捕。 这样的化合物将锁定为顺式折叠构象和 将洞悉拮抗剂相互作用的性质 从生物学数据中评估的H2受体位点。 功效 这些化合物中的H2受体拮抗剂将通过 涉及H2特异性组织（例如胃）的药理方案 粘膜，豚鼠右心房和大鼠子宫。 相对结合 亲和力（PA2）将根据表现出的剂量反应曲线计算 组胺H2位点的竞争性拮抗作用是合成化合物的。 这些大环化合物的构象分析将通过 分子力学和分子轨道技术的使用以及 光谱和晶体学方法。 的药理作用 组胺被认为是由至少两个不同的类别介导的 受体，指定为H1和H2，以特定的作用为特殊 组胺拮抗剂有选择地阻断组胺反应。 组胺显然在胃粘膜上起重要作用，光滑 肌肉，心肌，肾上腺髓质和某些神经过程，可能 在这些药理作用中涉及循环放大器作为第二信使。 组胺H2受体拮抗剂被广泛用作有效抑制剂 胃酸分泌在十二指肠溃疡和相关的治疗中 状况。 组胺受体对于控制心脏也很重要 速度。 似乎H2受体负责介导 组胺引起的愚蠢心律失常。 这可能很重要 对治疗心室心律不齐的影响 组胺释放。 目前，组胺的几何需求 H2受体拮抗剂是模棱两可的。 绑定位点几何形状都不 对拮抗剂有效吸收的要求也不是 理解。 组胺H2受体拮抗剂的大环类似物 将有助于理解拮抗剂相互作用的性质 使用H2受体站点，并将提供有关 这些药物的几何和构象要求。 显而易见 构象相关的结合亲和力关系应提供洞察力 用于进一步的组胺H2受体研究。