DITOLYL GUANIDINE ANALOGS AS ANTIPSYCHOTIC DRUGS

这个项目的目标是开发一种新的药物治疗方法 产生锥体外系的可能性最小的精神分裂症 副作用，迟发性运动障碍，或镇静。一种共识已经出现 在动物和人类的受体研究和行为实验中， Sigma受体可能介导某些药物诱导(苯并吗？，PCP) 以及对……的行为负责 氟哌啶醇和一些新提出的抗精神病药物。我们有独家的 全球范围内获得一系列Di-Ortho类似物的专利许可权- 甲苯基胍(DTG)，一种选择性最强的西格玛受体 配基。 在这个项目的第一阶段，我们成功地描述了最有希望的 DTG类似物具有受体特异性和血脑屏障通透性。 对于几种化合物，我们还放大了化学合成和 在动物试验中产生了抗精神病作用的证据， 副作用责任。 该项目第二阶段的目标是进一步描述Lead 以生物化学和生理方式合成的化合物将有助于 发展进程。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，化学分析，药理，安全性和 新陈代谢研究和全面毒性测试。

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.