Doulut S, Dubuc I, Rodriguez M, Vecchini F, Fulcrand H, Barelli H, Checler F, Bourdel E, Aumelas A, Lallement J C
CCIPE-Faculté de Pharmacie, Montpellier, France.
J Med Chem. 1993 May 14;36(10):1369-79. doi: 10.1021/jm00062a009.
The synthesis of N-[3-[(hydroxyamino) carbonyl]-1-oxo-2(R)-benzylpropyl]-L-isoleucyl-L-leucine (JMV-390-1, 6a), a multipeptidase inhibitor based on the C-terminal sequence common to neurotensin (NT) and neuromedin N (NN), is described. This compound behaves as a full inhibitor of the major NT/NN degrading enzymes in vitro, e.g. endopeptidase 24.16, endopeptidase 24.15, endopeptidase 24.11, and leucine aminopeptidase (type IV-S), in the nanomolar range (IC50's from 30 to 60 nM). Compound 6a was found to increase endogenous recovery of NT and NN from slices of mice hypothalamus depolarized with potassium. In various assays commonly used to select analgesics, e.g. hot-plate test, tail-flick test, acetic acid-induced writhing test, in mice, compound 6a proved to be potent when intracerebroventricularly (icv) injected. The analgesic effects observed were totally (hot-plate test) or largely (tail-flick test) reversed by the opioid antagonist naltrexone. Furthermore, icv injection of compound 6a (10 micrograms/mouse) was found to significantly potentiate the hypothermic effects of NT or NN.
描述了基于神经降压素（NT）和神经介素N（NN）共有的C末端序列的多肽酶抑制剂N-[3-[(羟基氨基)羰基]-1-氧代-2(R)-苄基丙基]-L-异亮氨酰-L-亮氨酸（JMV-390-1，6a）的合成。该化合物在体外对主要的NT/NN降解酶表现为完全抑制剂，例如内肽酶24.16、内肽酶24.15、内肽酶24.11和亮氨酸氨肽酶（IV-S型），在纳摩尔范围内（IC50为30至60 nM）。发现化合物6a可增加用钾去极化的小鼠下丘脑切片中NT和NN的内源性回收率。在常用于筛选镇痛药的各种试验中，例如热板试验、甩尾试验、乙酸诱导的扭体试验中，在小鼠中，化合物6a经脑室内（icv）注射后证明具有效力。观察到的镇痛作用被阿片类拮抗剂纳曲酮完全（热板试验）或大部分（甩尾试验）逆转。此外，发现icv注射化合物6a（10微克/小鼠）可显著增强NT或NN的降温作用。
