JTP-4819: a novel prolyl endopeptidase inhibitor with potential as a cognitive enhancer.
JTP-4819 ((S)-2-[[(S)-2-(hydroxyacetyl)-1-pyrrolidinyl]carbonyl]-N- phenylmethyl)-1-pyrrolidinecarboxamide) is a potent (IC50: 0.83 +/- 0.09 nM in rat brain supernatant; 5.43 +/- 0.81 nM in Flavobacterium meningosepticum) and specific inhibitor of prolyl endopeptidase (PEP). JTP-4819 (3 mg/kg p.o.) exhibited a strong and durable ex vivo inhibitory effect on PEP in various regions of the rat brain. In addition, JTP-4819 inhibited the degradation of substance P, arginine-vasopressin, thyrotropin-releasing hormone, neurotensin, oxytocin, bradykinin, and angiotensin II by purified PEP with IC50 values of 9.6, 13.9, 10.7, 14.0, 4.5, 7.6 and 10.6 nM, respectively. In the one-trial passive avoidance test in rats with scopolamine-induced amnesia, JTP-4819 significantly prolonged the retention time when administered orally at doses of 1 and 3 mg/kg 1 hr before acquisition or at 3 and 10 mg/kg 1 hr before retention. In addition, coadministration of JTP-4819 and substance P, arginine-vasopressin or thyrotropin-releasing hormone (at doses at which each drug alone did not prolong the retention time) improved the retention time of rats with scopolamine-induced amnesia. Microdialysis studies demonstrated that JTP-4819 caused a significant increase in ACh release in the frontal cortex and hippocampus of young rats at oral doses of 1 and 3 mg/kg, as well as in both brain regions of aged rats at a dose of 3 mg/kg. These results indicate that JTP-4819 potentiates neuropeptide functions inhibiting PEP, that it activates cholinergic transmission and that it enhances learning and memory.
Toide
K
K
Central Pharmaceutical Research Institute, Japan Tobacco Inc., Osaka.
Iwamoto
Y
Y
Fujiwara
T
T
Abe
H
H
D000109:Acetylcholine / Q000378:metabolism; D000375:Aging / Q000378:metabolism; D000818:Animals; D001362:Avoidance Learning / Q000187:drug effects; D003071:Cognition / Q000187:drug effects*; D003072:Cognition Disorders / Q000139:chemically induced / Q000188:drug therapy; D005417:Flavobacterium / Q000201:enzymology; D005625:Frontal Lobe / Q000187:drug effects / Q000378:metabolism; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D006868:Hydrolysis; D008297:Male; D017551:Microdialysis; D009479:Neuropeptides / Q000008:administration & dosage / Q000378:metabolism / Q000627:therapeutic use; D000085822:Prolyl Oligopeptidases; D011759:Pyrrolidines / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D011916:Rats, Inbred F344; D017208:Rats, Wistar; D012601:Scopolamine / Q000633:toxicity; D012697:Serine Endopeptidases / Q000378:metabolism*; D015842:Serine Proteinase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D013379:Substrate Specificity
D009479:Neuropeptides; D011759:Pyrrolidines; D015842:Serine Proteinase Inhibitors; C094211:JTP 4819; D012601:Scopolamine; D012697:Serine Endopeptidases; D000085822:Prolyl Oligopeptidases; D000109:Acetylcholine