Back to Search
Start Over
A novel selective positive allosteric modulator of metabotropic glutamate receptor subtype 5 has in vivo activity and antipsychotic-like effects in rat behavioral models.
- Source :
-
The Journal of pharmacology and experimental therapeutics [J Pharmacol Exp Ther] 2005 Apr; Vol. 313 (1), pp. 199-206. Date of Electronic Publication: 2004 Dec 17. - Publication Year :
- 2005
-
Abstract
- We found that 3-cyano-N-(1,3-diphenyl-1H-pyrazol-5-yl)benzamide (CDPPB) is a potent and selective positive allosteric modulator of the metabotropic glutamate receptor subtype 5 (mGluR5). In Chinese hamster ovary cells expressing human mGluR5, CDPPB potentiated threshold responses to glutamate in fluorometric Ca2+ assays more than 7-fold with an EC50 value of approximately 27 nM. At 1 microM, CDPPB shifted mGluR5 agonist concentration response curves to glutamate, quisqualate, and (R,S)-3,5-dihydroxyphenylglycine 3- to 9-fold to the left. At higher concentrations, CDPPB exhibited agonist-like activity on cells expressing mGluR5. No other activity was observed on any other mGluR or cell type at concentrations up to 10 microM. CDPPB had no effect on [3H]quisqualate binding to mGluR5 but did compete for binding of [3H]methoxyPEPy, an analog of the selective mGluR5 negative allosteric modulator MPEP. CDPPB was found to be brain penetrant and reversed amphetamine-induced locomotor activity and amphetamine-induced deficits in prepulse inhibition in rats, two models sensitive to antipsychotic drug treatment. These results demonstrate that positive allosteric modulation of mGluR5 produces behavioral effects, suggesting that such modulation serves as a viable approach to increasing mGluR5 activity in vivo. These effects are consistent with the hypothesis that allosteric potentiation of mGluR5 may provide a novel approach for development of antipsychotic agents.
- Subjects :
- ATP Binding Cassette Transporter, Subfamily B, Member 1 metabolism
Amino Acids pharmacology
Amphetamine antagonists & inhibitors
Amphetamine pharmacology
Animals
Antipsychotic Agents pharmacokinetics
Benzamides pharmacokinetics
CHO Cells
Cell Line
Central Nervous System Stimulants antagonists & inhibitors
Central Nervous System Stimulants pharmacology
Cricetinae
Dogs
Excitatory Amino Acid Antagonists pharmacology
Female
Haplorhini
Humans
Image Interpretation, Computer-Assisted
In Vitro Techniques
Microsomes, Liver metabolism
Models, Statistical
Motor Activity drug effects
Phthalimides pharmacokinetics
Radioligand Assay
Rats
Rats, Sprague-Dawley
Receptor, Metabotropic Glutamate 5
Receptors, Metabotropic Glutamate antagonists & inhibitors
Reflex, Startle drug effects
Xanthenes pharmacology
Antipsychotic Agents pharmacology
Behavior, Animal drug effects
Benzamides pharmacology
Phthalimides pharmacology
Receptors, Metabotropic Glutamate drug effects
Subjects
Details
- Language :
- English
- ISSN :
- 0022-3565
- Volume :
- 313
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- The Journal of pharmacology and experimental therapeutics
- Publication Type :
- Academic Journal
- Accession number :
- 15608073
- Full Text :
- https://doi.org/10.1124/jpet.104.079244