Novel Neurotensin Analogs as Antischizoprenics

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]作为内源性神经抑制剂发挥作用。因此，穿过血脑屏障的稳定的NT衍生物具有开发为预期不显示与多巴胺能药物相关的不良副作用的一类新的非多巴胺抗精神病药的显著潜力。文献中最好的NT衍生物[8-13]在很小程度上（<1%）穿过BBB，并失去对NT-I受体的100倍以上的结合亲和力。其中一种化合物在临床试验中作为抗精神分裂症药物，后来由于缺乏静脉注射活性而被放弃。使用我们的专利技术来改善肽作为药物实体，我们已经合成和研究了大约30种不同的NT [8-13]衍生物，这些衍生物大大改善了早期的化合物：维持或超过NT受体结合亲和力，当静脉注射时，化合物表现出高达50%的CNS生物利用度，它们在血清中的半衰期从几分钟增加到几小时，并且已经观察到对每种单独NT受体的选择性。在目前的提案中，我们寻求资金：a）合成和研究12个“第二代”化合物，预计将显示出更好的性能和B）评估我们最活跃的和代表性的化合物在两个关键的预测行为模型的精神分裂症：a）拮抗阿扑吗啡逆转前脉冲抑制的声惊吓，B）阻断运动活性兴奋作用的D-安非他明。从这些研究中出现的最好的化合物将作为一类新的抗精神分裂症药物开发。

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.