Hadden M Kyle, Orwig Kevin S, Kokko Kyle P, Mazella Jean, Dix Thomas A
Department of Pharmaceutical Sciences, Medical University of South Carolina, 280 Calhoun Street, PO Box 250140, Charleston, SC 29425, USA.
Neuropharmacology. 2005 Dec;49(8):1149-59. doi: 10.1016/j.neuropharm.2005.06.010. Epub 2005 Aug 10.
Neurotensin (NT) and its active fragment NT(8-13) elicit behavioral responses typical of clinically used antipsychotic drugs when administered directly to the brain. However, limited peptide stability and oral bioavailability have prevented these compounds from being developed as relevant pharmaceuticals. Recently, our laboratory designed and studied a first-generation NT(8-13) derivative, KK13, that elicited key pharmacokinetic and behavioral responses typical of clinically used antipsychotic drugs when administered to rats parenterally. This compound was the basis for the rational design of a series of second-generation NT(8-13) analogues (KH1-KH30) studied in this paper. Initial screening of these analogues for CNS activity by monitoring hypothermia induction after peripheral administration defined several compounds (KH11, KH24, KH26, and KH28-KH30) that warranted further investigation. Each compound maintained binding affinity for NTR(1), however, only KH24, KH26, and KH28 (as well as KK13) elicited significant hypothermic responses after oral administration. Of these, KH28 demonstrated an oral activity 3-fold greater than any other analogue; hence it was further characterized in a series of rat behavioral assays. KH28 attenuated d-amphetamine induced hyperlocomotion, a hallmark of current clinically effective antipsychotic drugs, after both IP and oral administration. In addition, tolerance to the compound did not develop after repeated daily dosing, as measured by hypothermic induction as well as attenuation of d-amphetamine induced hyperlocomotion. Finally, KH28 did not produce catalepsy, a deleterious side-effect elicited by classical antipsychotic drugs. KH28 is considered to be an ideal compound for further development as a potential novel antipsychotic.
神经降压素（NT）及其活性片段NT(8 - 13)直接注入大脑时会引发临床上使用的抗精神病药物所具有的典型行为反应。然而，肽的稳定性有限以及口服生物利用度低阻碍了这些化合物被开发成相关药物。最近，我们实验室设计并研究了第一代NT(8 - 13)衍生物KK13，当经肠胃外给药给大鼠时，它引发了临床上使用的抗精神病药物所具有的关键药代动力学和行为反应。该化合物是本文中所研究的一系列第二代NT(8 - 13)类似物（KH1 - KH30）合理设计的基础。通过监测外周给药后的体温降低情况对这些类似物进行中枢神经系统活性的初步筛选，确定了几种值得进一步研究的化合物（KH11、KH24、KH26以及KH28 - KH30）。每种化合物对NTR(1)都保持着结合亲和力，然而，只有KH24、KH26和KH28（以及KK13）在口服给药后引发了显著的体温降低反应。其中，KH28的口服活性比任何其他类似物都高3倍；因此，在一系列大鼠行为试验中对其进行了进一步表征。KH28在腹腔注射和口服给药后，均减弱了d - 苯丙胺诱导的运动亢进，这是目前临床上有效抗精神病药物的一个标志。此外，通过体温降低诱导以及对d - 苯丙胺诱导的运动亢进的减弱来衡量，每日重复给药后对该化合物并未产生耐受性。最后，KH28并未产生僵住症，这是经典抗精神病药物引发的一种有害副作用。KH28被认为是作为一种潜在新型抗精神病药物进一步开发的理想化合物。
