Novel Neurotensin Analogs as Antischizoprenics

描述（由申请人提供）：脑肽神经紧张素（NT）及其活性衍生物NT[8-13]具有内源性神经抑制剂的功能。因此，作为一种新的非多巴胺类抗精神病药物，稳定的NT衍生物通过血脑屏障具有重要的发展潜力，预计不会出现与多巴胺能相关的不良副作用。文献中最好的NT衍生物[8-13]只在很小程度上（< 1%）穿过血脑屏障，并且对NT- i受体失去超过100倍的结合亲和力。其中一种化合物在临床试验中被用作抗精神分裂症药物，但由于缺乏l.V.活性而被放弃。利用我们的专利技术将多肽作为药物实体进行改进，我们已经合成并研究了大约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，当注射l.V时，这些化合物显示出高达50%的中枢神经系统生物利用度，它们在血清中的半衰期从几分钟增加到几小时，并且观察到每种单独的NT受体的选择性。在目前的提案中，我们寻求资金来：a)合成和研究12种预计表现出更好性能的“第二代”化合物；b)评估我们在精神分裂症的两个关键预测行为模型中最具活性和代表性的化合物：a)拮抗阿波啡逆转声惊吓的脉冲前抑制；b)阻断d -安非他明的运动活动刺激作用。从这些研究中产生的最佳化合物将作为一类新的抗精神分裂症药物被开发。

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.