Effects of a novel metabotropic glutamate receptor 7 negative allosteric modulator, 6-(4-methoxyphenyl)-5-methyl-3-pyridin-4-ylisoxazonolo[4,5-c]pyridin-4(5H)-one (MMPIP), on the central nervous system in rodents.
We recently identified 6-(4-methoxyphenyl)-5-methyl-3-pyridin-4-ylisoxazolo[4,5-c]pyridin-4(5H)-one (MMPIP), the first allosteric metabotropic glutamate (mGlu) 7 receptor-selective negative allosteric modulator. In this study, we examined the in vivo pharmacological effects of MMPIP on the central nervous system. MMPIP was distributed into the brain after systemic administration in both mice and rats. Pharmacokinetic study revealed that the half-life of MMPIP in circulation was about 1h in rats. Results of various behavioral studies revealed that MMPIP impaired non-spatial and spatial cognitive performances in the object recognition test and the object location test in mice, respectively. In rats, MMPIP increased time to complete the task in the 8-arm radial maze test without increasing error. In addition to impairing cognition, MMPIP decreased social interaction with reduction of line crossing in rats, while MMPIP had no effects on locomotor activity in rats and mice, rota-rod performance in mice, prepulse inhibition in rats, maternal separation-induced ultrasonic vocalization in rat pups, stress-induced hyperthermia in mice, or the tail suspension test in mice. No analgesic effects of MMPIP were detected in either the tail immersion test or formalin test in mice. MMPIP did not alter the threshold for induction of seizures by electrical shock or pentylenetetrazole in mice. These findings suggest that blockade of mGlu(7) receptors by MMPIP may modulate both non-spatial and spatial cognitive functions without non-selective inhibitory effects on the central nervous system.
Hikichi
Hirohiko
H
Tsukuba Research Institute, Banyu Pharmaceutical Co., Ltd., 3 Okubo, Tsukuba, Ibaraki 300-2611, Japan. hirohiko.hikichi@po.rd.taisho.co.jp
Murai
Takeshi
T
Okuda
Shoki
S
Maehara
Shunsuke
S
Satow
Akio
A
Ise
Satoko
S
Nishino
Miho
M
Suzuki
Gentaroh
G
Takehana
Hiroshi
H
Hata
Mikiko
M
Ohta
Hisashi
H
D000494:Allosteric Regulation / Q000187:drug effects / Q000502:physiology; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects / Q000502:physiology; D002490:Central Nervous System / Q000187:drug effects* / Q000502:physiology; D003071:Cognition; D004554:Electric Countershock; D018691:Excitatory Amino Acid Antagonists / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D005334:Fever; D008124:Locomotion; D008297:Male; D018782:Maze Learning; D051379:Mice; D008813:Mice, Inbred ICR; D010433:Pentylenetetrazole; D011728:Pyridones / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D018094:Receptors, Metabotropic Glutamate / Q000037:antagonists & inhibitors* / Q000378:metabolism; D012377:Rodentia / Q000502:physiology; D014465:Ultrasonics; D014828:Vocalization, Animal
C553164:6-(4-methoxyphenyl)-5-methyl-3-pyridin-4-ylisoxazonolo(4,5-c)pyridin-4(5H)-one; D018691:Excitatory Amino Acid Antagonists; D011728:Pyridones; D018094:Receptors, Metabotropic Glutamate; C102719:metabotropic glutamate receptor 7; D010433:Pentylenetetrazole