Toide K, Fujiwara T, Iwamoto Y, Shinoda M, Okamiya K, Kato T
Central Pharmaceutical Research Institute, Japan Tobacco Inc., Osaka, Japan.
Naunyn Schmiedebergs Arch Pharmacol. 1996 Feb;353(3):355-62. doi: 10.1007/BF00168640.
The effect of a novel prolyl endopeptidase (PEP) inhibitor, (S)-2-[[(S)-2-(hydroxyacetyl)-1-pyrrolidinyl] carbonyl]-N-(phenylmethyl)-1-pyrrolidine-carboxamide (JTP-4819), on neuropeptide metabolism was investigated in the rat brain. JTP-4819 exhibited a strong in vitro inhibitory effect on cortical and hippocampal PEP activity, with the IC50 values being approximately 0.58 +/- 0.02 and 0.61 +/- 0.06 nM, respectively. JTP-4819 also inhibited the in vitro degradation of substance P (SP), arginine-vasopressin (AVP), and thyrotropin-releasing hormone (TRH) by rat brain supernatants, with the IC50 values being respectively 3.4, 2.1, and 1.4 nM in the cerebral cortex and 3.3, 2.8, and 1.9 nM in the hippocampus. Oral administration of JTP-4819 at doses of 1 and 3 mg/kg increased SP-like immunoreactivity (LI) and AVP-LI in the cerebral cortex. JTP-4819 also increased hippocampal SP-LI and AVP-LI at doses of 1 and 3 mg/kg, as well as hippocampal TRH-LI at a dose of 3 mg/kg. These findings suggest that JTP-4819 inhibited the degradation of SP, AVP, and TRH in the rat brain secondary to the inhibition of PEP, and thus increased cortical and hippocampal SP-LI and AVP-LI as well as hippocampal TRH-LI.
在大鼠脑中研究了一种新型脯氨酰内肽酶（PEP）抑制剂（S）-2-[[（S）-2-（羟基乙酰基）-1-吡咯烷基]羰基]-N-（苯甲基）-1-吡咯烷甲酰胺（JTP-4819）对神经肽代谢的影响。JTP-4819在体外对皮质和海马PEP活性表现出强烈的抑制作用，IC50值分别约为0.58±0.02和0.61±0.06 nM。JTP-4819还抑制大鼠脑匀浆上清液对P物质（SP）、精氨酸加压素（AVP）和促甲状腺激素释放激素（TRH）的体外降解，在大脑皮质中的IC50值分别为3.4、2.1和1.4 nM，在海马中的IC50值分别为3.3、2.8和1.9 nM。以1和3 mg/kg的剂量口服JTP-4819可增加大脑皮质中SP样免疫反应性（LI）和AVP-LI。JTP-4819以1和3 mg/kg的剂量还可增加海马中的SP-LI和AVP-LI，以及以3 mg/kg的剂量增加海马中的TRH-LI。这些发现表明，JTP-4819通过抑制PEP继发性地抑制大鼠脑中SP、AVP和TRH的降解，从而增加了皮质和海马中的SP-LI和AVP-LI以及海马中的TRH-LI。
