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）：脑肽神经辛（NT）及其活性衍生物NT [8-13]的发挥作用。因此，越过血脑屏障的稳定的NT衍生物具有发育的巨大潜力，因为新的非肾上腺素抗精神病药期望不显示与多巴胺能相关的不良副作用。 NT [8-13]的最佳文献衍生物在较小程度上越过BBB（<1％），对NT-I受体的结合亲和力却大于100倍以上。这些化合物之一是在临床试验中作为一种抗精神病药，然后由于缺乏L.V.活动。使用我们的专利技术改善肽作为药物实体，我们已经合成并研究了大约30种不同的NT [8-13]衍生物[8-13]衍生物，这些衍生物可在早期化合物上大大改进：NT受体结合亲和力是维持或超过的，这些化合物在L.V.时表现出高达50％的CNS生物利用率。注射后，它们在血清中的半衰期已从数分钟内增加到数小时，并且已经观察到了每个单个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“第二代”化合物，预计将显示出更好的特性，b）评估我们在两个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）拮抗呼吸暂停的逆转逆转逆转抑制声学的刺激性刺激性活动，b）受到刺激性的影响，b）受到刺激性的影响。这些研究中出现的最佳化合物将有望作为新的抗腐殖剂剂进行开发。