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Novel Neurotensin Analogs as Antischizoprenics

作为抗精神分裂药的新型神经降压素类似物

基本信息

批准号：
6549606
负责人：
THOMAS A DIX
金额：
$ 13.95万
依托单位：
ARGOLYN BIOSCIENCE, INC.
依托单位国家：
美国
项目类别：
财政年份：
2002
资助国家：
美国
起止时间：
2002-09-26 至 2003-09-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/6549606
关键词：
amphetamines antipsychotic agents apomorphine biomimetics drug design /synthesis /production hormone receptor laboratory rat neurotensin peptide analog peptide chemical synthesis receptor binding schizophrenia

项目摘要

DESCRIPTION (provided by applicant): The brain peptide neurotensin (NT) and its active derivative NT [8-13] function as endogenous neuroleptics. Stable NT derivatives that cross the blood brain barrier therefore have significant potential for development as a new class of non-dopamineric antipsychotics expected not to display the adverse side effects associated with the dopaminergics. The best literature derivatives of NT [8-13] cross the BBB to a small extent (< 1 percent) and lose greater than 100-fold binding affinity for the NT-I receptor. One of these compounds was in clinical trials as an antischizophrenic before being dropped due to lack of l.V. activity. Using our patented technology for improving peptides as drug entities, we have synthesized and studied about 30 different NT [8-13] derivatives that drastically improve upon earlier compounds: NT receptor binding affinity is maintained or exceeded, the compounds exhibit up to 50 percent CNS bioavailability when l.V. Injected, their half-lives in serum have been increased from minutes to hours, and selectivities for each of the individual NT receptors has been observed. In the current proposal, we seek funding to: a) synthesize and study 12 "second generation" compounds predicted to show even better properties and b) evaluate our most active and representative compounds in two key predictive behavioral models of schizophrenia: a) antagonizing apomorphine reversal of prepulse inhibition of acoustic startle, b) blocking the locomotor activity stimulant effect of D-amphetamine. The best compounds emerging from these studies will be poised for development as a new class of antischizophrenic agents.

描述（由申请人提供）：脑肽神经降压素（NT）及其活性衍生物NT[8-13]起到内源性精神安定药的作用。因此，能够穿过血脑屏障的稳定 NT 衍生物作为一类新型非多巴胺抗精神病药具有巨大的开发潜力，预计不会表现出与多巴胺能药物相关的不良副作用。 NT [8-13] 的最佳文献衍生物会在较小程度上（< 1%）穿过 BBB，并且对 NT-1 受体的结合亲和力损失超过 100 倍。其中一种化合物作为抗精神分裂症药物正在进行临床试验，但由于缺乏左心室容量而被放弃。活动。利用我们改进肽作为药物实体的专利技术，我们合成并研究了约 30 种不同的 NT [8-13] 衍生物，这些衍生物大大改进了早期化合物：NT 受体结合亲和力得以维持或超过，这些化合物在静脉注射时表现出高达 50% 的 CNS 生物利用度。注射后，它们在血清中的半衰期从几分钟延长到几小时，并且观察到对每种 NT 受体的选择性。在当前的提案中，我们寻求资金：a）合成和研究12种预计表现出更好特性的“第二代”化合物，b）在精神分裂症的两个关键预测行为模型中评估我们最活跃和最具代表性的化合物：a）拮抗阿扑吗啡逆转声惊吓的前脉冲抑制，b）阻断D-安非他明的运动活动刺激作用。这些研究中出现的最佳化合物将有望作为一类新型抗精神分裂症药物进行开发。