Effect of a novel prolyl endopeptidase inhibitor, JTP-4819, on neuropeptide metabolism in the rat brain.
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.
Toide
K
K
Central Pharmaceutical Research Institute, Japan Tobacco Inc., Osaka, Japan.
Fujiwara
T
T
Iwamoto
Y
Y
Shinoda
M
M
Okamiya
K
K
Kato
T
T
D000284:Administration, Oral; D000544:Alzheimer Disease / Q000201:enzymology / Q000209:etiology; D000818:Animals; D001127:Arginine Vasopressin / Q000378:metabolism; D002540:Cerebral Cortex / Q000187:drug effects* / Q000201:enzymology; D004305:Dose-Response Relationship, Drug; D006624:Hippocampus / Q000187:drug effects* / Q000201:enzymology; D009479:Neuropeptides / Q000378:metabolism*; D000085822:Prolyl Oligopeptidases; D011759:Pyrrolidines / Q000008:administration & dosage / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D012697:Serine Endopeptidases / Q000378:metabolism*; D015842:Serine Proteinase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D013373:Substance P / Q000378:metabolism; D013973:Thyrotropin-Releasing Hormone / Q000378:metabolism
D009479:Neuropeptides; D011759:Pyrrolidines; D015842:Serine Proteinase Inhibitors; D001127:Arginine Vasopressin; D013373:Substance P; D013973:Thyrotropin-Releasing Hormone; C094211:JTP 4819; D012697:Serine Endopeptidases; D000085822:Prolyl Oligopeptidases