Hirohiko Hikichi

Pharmacological Effects of the Metabotropic Glutamate Receptor 1 Antagonist Compared with Those of the Metabotropic Glutamate Receptor 5 Antagonist and Metabotropic Glutamate Receptor 2/3 Agonist in Rodents: Detailed Investigations with a Selective Allosteric Metabotropic Glutamate Receptor 1 Antagonist, FTIDC [4-[1-(2-Fluoropyridine-3-yl)-5-methyl-1H-1,2,3-triazol-4-yl]-N-isopropyl-N-methyl-3,6-dihydropyridine-1(2H)-carboxamide]

The functional roles of metabotropic glutamate receptor (mGluR) 1 in integrative brain functions were investigated using a potent and selective mGluR1 allosteric antagonist, FTIDC [4-[1-(2-fluoropyridine-3-yl)-5-methyl-1H-1,2,3-triazol-4-yl]-N-isopropyl-N-methyl-3,6-dihydropyridine-1(2H)-carboxamide], in comparison with the mGluR5 allosteric antagonist and the mGluR2/3 orthosteric agonist in rodents. FTIDC reduced maternal separation-induced ultrasonic vocalization and stress-induced hyperthermia without affecting behaviors in the elevated plus maze. An mGluR5 antagonist, 2-methyl-6-(phenylethynyl)-pyridine (MPEP), and an mGluR2/3 agonist, LY379268 [(1R,4R,5S,6R)-4-amino-2-oxabicyclo[3.1.0]hexane-4,6-dicarboxylic acid], showed anxiolytic activities in these models, suggesting involvement of postsynaptic mGluR1 in stress-related responses comparable with mGluR5 and mGluR2/3. Analgesic effects of FTIDC were seen in the formalin test but not in the tail immersion test. FTIDC selectively blocked methamphetamine-induced hyperlocomotion and disruption of prepulse inhibition, whereas MPEP and LY379268 did not alter those behaviors, suggesting that pharmacological blockade of mGluR1 could result in antipsychotic-like effects. FTIDC did not elicit catalepsy or impair motor functions at 10 times higher dose than doses showing antipsychotic-like action. In conclusion, blockade of mGluR1 showed antipsychotic-like effects without impairing motor functions, whereas blockade of mGluR5 and activation of mGluR2/3 did not display such activities.

Discovery and biological profile of isoindolinone derivatives as novel metabotropic glutamate receptor 1 antagonists: A potential treatment for psychotic disorders

We describe here the discovery and biological profile of a series of isoindolinone derivatives as developed mGluR1 antagonists. Our combined strategy of rapid parallel synthesis and conventional medicinal optimization successfully led to N-cyclopropyl 22 and N-isopropyl isoindolinone analogs 21 and 23 with improved in vivo DMPK profiles. Moreover the most advanced analog 23 showed an oral antipsychotic-like effect at a dose of 1mg/kg in an animal model.

Discovery and biological profile of 4-(1-aryltriazol-4-yl)-tetrahydropyridines as an orally active new class of metabotropic glutamate receptor 1 antagonist.

We describe here the discovery and the structure-activity relationship (SAR) of a series of 4-(1-Aryltriazol-4-yl)-tetrahydropyridines as novel mGluR1 antagonists. Our extensive chemical modification of lead compound 2 successfully led to fluoropyridine analogs 7j and 1 with improved in vivo antagonistic activities. Among the evaluated compounds, chemically stable urea analog 1 showed oral antagonistic activity at dose ranges of 10-30mg/kg in an animal model.

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.

Face-washing behavior induced by the group I metabotropic glutamate receptor agonist (S)-3,5-DHPG in mice is mediated by mGlu1 receptor.

It is known for the non-selective group I metabotropic glutamate (mGlu) receptors agonist (S)-3,5-dihydroxyphenylglycine (S-3,5-DHPG) to cause convulsions, which are mediated by mGlu1 receptor. However, the behavioral changes other than convulsions caused by (S)-3,5-DHPG have not been well studied. The purpose of the present study was to explore the behavioral changes elicited by activation of group I mGlu receptors with (S)-3,5-DHPG and to clarify which, mGlu1 receptor or mGlu5 receptor, is responsible for such behavior. (S)-3,5-DHPG at doses of 3-30 nmol caused characteristic face-washing behavior. This behavioral change was inhibited by both the competitive mGlu1 receptor antagonists (RS)-1-aminoindan-1,5-dicarboxylic acid (AIDA) and (S)-4-carboxyphenylglycine (S-4CPG) and the non-competitive mGlu1 receptor antagonist, 4-[1-(2-fluoropyridin-3-yl)-5-methyl-1H-1,2,3-triazol-4-yl]-N-isopropyl-N-methyl-3,6-dihydropyridine-1(2H)-carboxamide (FTIDC), but not by the mGlu5 receptor antagonist 2-Methyl-6-(phenylethynyl)pyridine hydrochloride (MPEP), the mGlu2/3 receptor agonist (-)-2-oxa-4-aminobicyclo[3.1.0]hexane-4,6-dicarboxylate (LY379268), the mGlu2/3 receptor antagonist (2S)-2-amino-2-[(1S,2S)-2-carboxycycloprop-1-yl]-3-(xanth-9-yl) propanoic acid (LY341495), the N-methyl-d-asparate (NMDA) receptor antagonist 5R,10S-(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine hydrogen maleate (MK-801), or the competitive non-NMDA receptor antagonist 2,3-dioxo-6-nitro-1,2,3,4-tetrahydrobenzo[f]quinoxaline-7-sulfonamide (NBQX). These findings indicate that face-washing behavior is due to selective activation of mGlu1 receptor by (S)-3,5-DHPG, and that the face-washing behavior induced by (S)-3,5-DHPG in mice can be used for in vivo testing of the antagonistic potency of both competitive and non-competitive mGlu1 receptor antagonists.

Antipsychotic effects of N-desmethylclozapine on sensorimotor gating function in rats — Possible involvement of activation of M1 muscarinic receptors

N-desmethylclozapine (NDMC), one of the major metabolites of clozapine, has been demonstrated to exhibit partial agonistic activity at M(1) muscarinic receptors in vitro. Behavioral effects of NDMC were examined to determine whether NDMC contributed to the antipsychotic effects of clozapine via activation of muscarinic receptors. Both NDMC (10-30 mg/kg) and its parent compound clozapine (3-10 mg/kg) antagonized the disruption of prepulse inhibition (PPI) caused by the indirect dopamine agonist methamphetamine (3 mg/kg) in rats. However, NDMC (30 mg/kg) did not increase plasma levels of prolactin in rats. The same dose ranges of NDMC antagonized the disruption of PPI caused by the N-methyl-D-aspartate receptor antagonist ketamine (5 mg/kg) in rats. Furthermore, NDMC in the same dose ranges antagonized the disruption of PPI caused by the muscarinic receptor antagonist scopolamine (0.3 mg/kg) in rats. These findings suggest that NDMC has potent antipsychotic effects in animal models to examine sensorimotor gating function, and that NDMC may act through the activation of a muscarinic receptor for the treatment of schizophrenia.

Behavioral effects of N-desmethylclozapine on locomotor activity and sensorimotor gating function in mice-Possible involvement of muscarinic receptors.

N-desmethylclozapine (NDMC), a major circulating metabolite of the atypical antipsychotic drug, clozapine, and has M(1) muscarinic receptor partial agonistic property. The purpose of the present study was to examine whether in vivo behavioral effects of NDMC were elicited through the activation of muscarinic receptors. Both a non-selective muscarinic receptor agonist, oxotremorine (0.01-0.1mg/kg), and an M(1) and M(4) muscarinic receptor agonist, xanomeline (0.3-3mg/kg), decreased exploratory locomotor activity in mice. This effect was significantly antagonized by a non-selective muscarinic receptor antagonist, scopolamine, at a dose of 0.3mg/kg without affecting exploratory locomotor activity by itself. NDMC (3-30mg/kg) also decreased exploratory locomotor activity in a dose-dependent manner, and the reduced locomotor activity was significantly antagonized by scopolamine at doses of 0.1 and 0.3mg/kg. These results suggested that NDMC might decrease exploratory locomotor activity at least partly through the activation muscarinic receptors in vivo. NDMC (10-30mg/kg) and clozapine (0.3-1mg/kg) dose-dependently increased prepulse inhibition (PPI) in DBA/2J mice, as did xanomeline (1-3mg/kg). Scopolamine at a dose of 0.3mg/kg without altering PPI by itself significantly antagonized the increase of PPI caused by NDMC (30mg/kg), xanomeline (3mg/kg), and oxotremorine (0.06mg/kg). These findings suggest that the activation of muscarinic receptors may be at least partly responsible for exerting the antipsychotic-like effects of both NDMC and xanomeline in an animal model for schizophrenia.

Role of K+ channels in the PACAP-induced catecholamine secretion from the rat adrenal gland.

We eluciated whether K+ channels modulate adrenal catecholamine secretion induced by pituitary adenylate cyclase-activating polypeptide (PACAP) in the isolated perfused rat adrenal gland. PACAP (100 nM) increased adrenal epinephrine output. The PACAP-induced responses were enhanced by treatment with apamin (10-100 nM) in a concentration-dependent manner. In the presence of nifedipine (3 microM), apamin (1 microM) did not enhance the PACAP-induced responses. Charybdotoxin (1-100 nM) had little influence on the PACAP-induced responses. These results suggest that small-conductance Ca2+-activated K+ channels interfere with L-type voltage-dependent Ca2+ channels to counteract the PACAP-induced adrenal catecholamine secretion.