DITOLYL GUANIDINE ANALOGS AS ANTIPSYCHOTIC DRUGS

作为抗精神病药的二甲苯基胍类似物

• 批准号: 3509014
• 负责人: JAMES B FISCHER
• 金额: $ 24.59万
• 依托单位: CAMBRIDGE NEUROSCIENCE
• 依托单位国家: 美国
• 财政年份: 1989
• 资助国家: 美国
• 起止时间: 1989-08-01 至 1992-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3509014
• 关键词: antipsychotic agents; blood brain barrier; chemical synthesis; dogs; drug adverse effect; drug design /synthesis /production; drug metabolism; drug screening /evaluation; extrapyramidal disorder; guanidines; inhibitor /antagonist; laboratory rat; lead; limbic system; mental disorder chemotherapy; opioid receptor; pharmacokinetics; radiotracer; receptor binding; schizophrenia; stimulant /agonist; tissue /cell culture

The goal of this project is to develop a novel drug treatment for schizophrenia that would have minimal liability to produce extrapyramidal side effects, tardive dyskinesia, or sedation. A consensus has emerged from receptor studies and behavioral experiments in animals and humans, that the sigma receptor may mediate some drug-induced (benzomorphan, PCP) psychotomimetic effects as well as be responsible for the actions of haloperidol and some newly proposed antipsychotic drugs. We have exclusive world-wide patent licensing rights to a series of analogs of Di-ortho- tolyl-guanidine (DTG), one of the most selective and potent sigma receptor ligands. In Phase I this project we succeeded in characterizing the most promising DTG analogs for receptor specificity and blood brain barrier permeability. With several of the compounds, we also scaled up the chemical synthesis and produced evidence, in animal tests, of antipsychotic effect with minimal side effect liability. The goals of Phase II of this project are to further characterize the lead compounds biochemically and physiologically in ways that will aid the development process. At the same time we will initiate the development steps necessary to obtain an IND. These will include bulk chemical synthesis, development of a chemical assay, pharmacology safety and metabolism studies and full-scale toxicity testing.

该项目的目标是开发一种新的药物治疗方法 精神分裂症产生锥体外系的可能性极小 副作用、迟发性运动障碍或镇静。 共识已经形成 来自动物和人类的受体研究和行为实验， 西格玛受体可能介导一些药物诱导的（苯并吗啡烷，PCP） 拟心理作用以及对以下行为负责 氟哌啶醇和一些新提出的抗精神病药物。 我们有独家的 Di-ortho- 一系列类似物的全球专利许可权 甲苯胍 (DTG)，最具选择性和最有效的 Sigma 受体之一 配体。 在这个项目的第一阶段，我们成功地描述了最有前途的 用于受体特异性和血脑屏障通透性的 DTG 类似物。 对于其中几种化合物，我们还扩大了化学合成和 在动物试验中提供了抗精神病作用的证据，且作用极小 副作用责任。 该项目第二阶段的目标是进一步确定领先地位 化合物的生化和生理学方式将有助于 发展过程。 同时我们将启动开发 获得 IND 所需的步骤。 这些将包括散装化学品 合成、化学测定的开发、药理学安全性和 代谢研究和全面毒性测试。