Characterization of the novel positive allosteric modulator of the metabotropic glutamate receptor 4 ADX88178 in rodent models of neuropsychiatric disorders

Mikhail Kalinichev, Emmanuel Le Poul, Christelle Boléa, Françoise Girard, Brice Campo, Massimiliano Fonsi, Isabelle Royer-Urios, Susan E. Browne, Jason M. Uslaner, Matthew J. Davis, Jacob Raber, Robert Duvoisin, Simon T. Bate, Ian J. Reynolds, Sonia Poli, Sylvain Celanire

Research output: Contribution to journalArticle

36 Citations (Scopus)

Abstract

There is growing evidence that activation of metabotropic glutamate receptor 4 (mGlu4) leads to anxiolytic- and antipsychotic-like efficacy in rodent models, yet its relevance to depression-like reactivity remains unclear. Here, we present the pharmacological evaluation of ADX88178 [5-methyl-N-(4-methylpyrimidin-2-yl)-4-(1H-pyrazol-4-yl)thiazol-2-amine], a novel potent, selective, and brain-penetrant positive allosteric modulator of the mGlu4 receptor in rodent models of anxiety, obsessive compulsive disorder (OCD), fear, depression, and psychosis. ADX88178 dose-dependently reduced the number of buried marbles in the marble burying test and increased open-arm exploration in the elevated plus maze (EPM) test, indicative of anxiolytic-like efficacy. Target specificity of the effect in the EPM test was confirmed using male and female mGlu4 receptor knockout mice. In mice, ADX88178 reduced the likelihood of conditioned freezing in the acquisition phase of the fear conditioning test, yet had no carryover effect in the expression phase. Also, ADX88178 dose-dependently reduced duration of immobility in the forced swim test, indicative of antidepressant-like efficacy. ADX88178 reduced DOI (2,5-dimethoxy-4-iodoamphetamine)-mediated head twitches (albeit with no dose-dependency), and MK-801 [(5S,10R)-(+)-5-methyl-10,11-dihydro-5H- dibenzo[a,d]cyclohepten-5,10-imine]-induced locomotor hyperactivity in mice, but was inactive in the conditioned avoidance response test in rats. The compound showed good specificity as it had no effect on locomotor activity in mice and rats at efficacious doses. Thus, allosteric activation of mGlu4 receptors can be a promising new therapeutic approach for treatment of anxiety, OCD, fear-related disorders, and psychosis.

Original languageEnglish (US)
Pages (from-to)495-505
Number of pages11
JournalJournal of Pharmacology and Experimental Therapeutics
Volume350
Issue number3
DOIs
StatePublished - 2014

Fingerprint

Rodentia
Fear
Calcium Carbonate
Obsessive-Compulsive Disorder
Anti-Anxiety Agents
Psychotic Disorders
Anxiety
Depression
Imines
Dizocilpine Maleate
Locomotion
Knockout Mice
Freezing
Antidepressive Agents
Antipsychotic Agents
5-methyl-N-(4-methylpyrimidin-2-yl)-4-(1H-pyrazol-4-yl)thiazol-2-amine
metabotropic glutamate receptor 4
Arm
Head
Pharmacology

ASJC Scopus subject areas

  • Pharmacology
  • Molecular Medicine

Cite this

Characterization of the novel positive allosteric modulator of the metabotropic glutamate receptor 4 ADX88178 in rodent models of neuropsychiatric disorders. / Kalinichev, Mikhail; Le Poul, Emmanuel; Boléa, Christelle; Girard, Françoise; Campo, Brice; Fonsi, Massimiliano; Royer-Urios, Isabelle; Browne, Susan E.; Uslaner, Jason M.; Davis, Matthew J.; Raber, Jacob; Duvoisin, Robert; Bate, Simon T.; Reynolds, Ian J.; Poli, Sonia; Celanire, Sylvain.

In: Journal of Pharmacology and Experimental Therapeutics, Vol. 350, No. 3, 2014, p. 495-505.

Research output: Contribution to journalArticle

Kalinichev, M, Le Poul, E, Boléa, C, Girard, F, Campo, B, Fonsi, M, Royer-Urios, I, Browne, SE, Uslaner, JM, Davis, MJ, Raber, J, Duvoisin, R, Bate, ST, Reynolds, IJ, Poli, S & Celanire, S 2014, 'Characterization of the novel positive allosteric modulator of the metabotropic glutamate receptor 4 ADX88178 in rodent models of neuropsychiatric disorders', Journal of Pharmacology and Experimental Therapeutics, vol. 350, no. 3, pp. 495-505. https://doi.org/10.1124/jpet.114.214437
Kalinichev, Mikhail ; Le Poul, Emmanuel ; Boléa, Christelle ; Girard, Françoise ; Campo, Brice ; Fonsi, Massimiliano ; Royer-Urios, Isabelle ; Browne, Susan E. ; Uslaner, Jason M. ; Davis, Matthew J. ; Raber, Jacob ; Duvoisin, Robert ; Bate, Simon T. ; Reynolds, Ian J. ; Poli, Sonia ; Celanire, Sylvain. / Characterization of the novel positive allosteric modulator of the metabotropic glutamate receptor 4 ADX88178 in rodent models of neuropsychiatric disorders. In: Journal of Pharmacology and Experimental Therapeutics. 2014 ; Vol. 350, No. 3. pp. 495-505.
@article{be69a58ceccf422190267a1348385991,
title = "Characterization of the novel positive allosteric modulator of the metabotropic glutamate receptor 4 ADX88178 in rodent models of neuropsychiatric disorders",
abstract = "There is growing evidence that activation of metabotropic glutamate receptor 4 (mGlu4) leads to anxiolytic- and antipsychotic-like efficacy in rodent models, yet its relevance to depression-like reactivity remains unclear. Here, we present the pharmacological evaluation of ADX88178 [5-methyl-N-(4-methylpyrimidin-2-yl)-4-(1H-pyrazol-4-yl)thiazol-2-amine], a novel potent, selective, and brain-penetrant positive allosteric modulator of the mGlu4 receptor in rodent models of anxiety, obsessive compulsive disorder (OCD), fear, depression, and psychosis. ADX88178 dose-dependently reduced the number of buried marbles in the marble burying test and increased open-arm exploration in the elevated plus maze (EPM) test, indicative of anxiolytic-like efficacy. Target specificity of the effect in the EPM test was confirmed using male and female mGlu4 receptor knockout mice. In mice, ADX88178 reduced the likelihood of conditioned freezing in the acquisition phase of the fear conditioning test, yet had no carryover effect in the expression phase. Also, ADX88178 dose-dependently reduced duration of immobility in the forced swim test, indicative of antidepressant-like efficacy. ADX88178 reduced DOI (2,5-dimethoxy-4-iodoamphetamine)-mediated head twitches (albeit with no dose-dependency), and MK-801 [(5S,10R)-(+)-5-methyl-10,11-dihydro-5H- dibenzo[a,d]cyclohepten-5,10-imine]-induced locomotor hyperactivity in mice, but was inactive in the conditioned avoidance response test in rats. The compound showed good specificity as it had no effect on locomotor activity in mice and rats at efficacious doses. Thus, allosteric activation of mGlu4 receptors can be a promising new therapeutic approach for treatment of anxiety, OCD, fear-related disorders, and psychosis.",
author = "Mikhail Kalinichev and {Le Poul}, Emmanuel and Christelle Bol{\'e}a and Fran{\cc}oise Girard and Brice Campo and Massimiliano Fonsi and Isabelle Royer-Urios and Browne, {Susan E.} and Uslaner, {Jason M.} and Davis, {Matthew J.} and Jacob Raber and Robert Duvoisin and Bate, {Simon T.} and Reynolds, {Ian J.} and Sonia Poli and Sylvain Celanire",
year = "2014",
doi = "10.1124/jpet.114.214437",
language = "English (US)",
volume = "350",
pages = "495--505",
journal = "Journal of Pharmacology and Experimental Therapeutics",
issn = "0022-3565",
publisher = "American Society for Pharmacology and Experimental Therapeutics",
number = "3",

}

TY - JOUR

T1 - Characterization of the novel positive allosteric modulator of the metabotropic glutamate receptor 4 ADX88178 in rodent models of neuropsychiatric disorders

AU - Kalinichev, Mikhail

AU - Le Poul, Emmanuel

AU - Boléa, Christelle

AU - Girard, Françoise

AU - Campo, Brice

AU - Fonsi, Massimiliano

AU - Royer-Urios, Isabelle

AU - Browne, Susan E.

AU - Uslaner, Jason M.

AU - Davis, Matthew J.

AU - Raber, Jacob

AU - Duvoisin, Robert

AU - Bate, Simon T.

AU - Reynolds, Ian J.

AU - Poli, Sonia

AU - Celanire, Sylvain

PY - 2014

Y1 - 2014

N2 - There is growing evidence that activation of metabotropic glutamate receptor 4 (mGlu4) leads to anxiolytic- and antipsychotic-like efficacy in rodent models, yet its relevance to depression-like reactivity remains unclear. Here, we present the pharmacological evaluation of ADX88178 [5-methyl-N-(4-methylpyrimidin-2-yl)-4-(1H-pyrazol-4-yl)thiazol-2-amine], a novel potent, selective, and brain-penetrant positive allosteric modulator of the mGlu4 receptor in rodent models of anxiety, obsessive compulsive disorder (OCD), fear, depression, and psychosis. ADX88178 dose-dependently reduced the number of buried marbles in the marble burying test and increased open-arm exploration in the elevated plus maze (EPM) test, indicative of anxiolytic-like efficacy. Target specificity of the effect in the EPM test was confirmed using male and female mGlu4 receptor knockout mice. In mice, ADX88178 reduced the likelihood of conditioned freezing in the acquisition phase of the fear conditioning test, yet had no carryover effect in the expression phase. Also, ADX88178 dose-dependently reduced duration of immobility in the forced swim test, indicative of antidepressant-like efficacy. ADX88178 reduced DOI (2,5-dimethoxy-4-iodoamphetamine)-mediated head twitches (albeit with no dose-dependency), and MK-801 [(5S,10R)-(+)-5-methyl-10,11-dihydro-5H- dibenzo[a,d]cyclohepten-5,10-imine]-induced locomotor hyperactivity in mice, but was inactive in the conditioned avoidance response test in rats. The compound showed good specificity as it had no effect on locomotor activity in mice and rats at efficacious doses. Thus, allosteric activation of mGlu4 receptors can be a promising new therapeutic approach for treatment of anxiety, OCD, fear-related disorders, and psychosis.

AB - There is growing evidence that activation of metabotropic glutamate receptor 4 (mGlu4) leads to anxiolytic- and antipsychotic-like efficacy in rodent models, yet its relevance to depression-like reactivity remains unclear. Here, we present the pharmacological evaluation of ADX88178 [5-methyl-N-(4-methylpyrimidin-2-yl)-4-(1H-pyrazol-4-yl)thiazol-2-amine], a novel potent, selective, and brain-penetrant positive allosteric modulator of the mGlu4 receptor in rodent models of anxiety, obsessive compulsive disorder (OCD), fear, depression, and psychosis. ADX88178 dose-dependently reduced the number of buried marbles in the marble burying test and increased open-arm exploration in the elevated plus maze (EPM) test, indicative of anxiolytic-like efficacy. Target specificity of the effect in the EPM test was confirmed using male and female mGlu4 receptor knockout mice. In mice, ADX88178 reduced the likelihood of conditioned freezing in the acquisition phase of the fear conditioning test, yet had no carryover effect in the expression phase. Also, ADX88178 dose-dependently reduced duration of immobility in the forced swim test, indicative of antidepressant-like efficacy. ADX88178 reduced DOI (2,5-dimethoxy-4-iodoamphetamine)-mediated head twitches (albeit with no dose-dependency), and MK-801 [(5S,10R)-(+)-5-methyl-10,11-dihydro-5H- dibenzo[a,d]cyclohepten-5,10-imine]-induced locomotor hyperactivity in mice, but was inactive in the conditioned avoidance response test in rats. The compound showed good specificity as it had no effect on locomotor activity in mice and rats at efficacious doses. Thus, allosteric activation of mGlu4 receptors can be a promising new therapeutic approach for treatment of anxiety, OCD, fear-related disorders, and psychosis.

UR - http://www.scopus.com/inward/record.url?scp=84905057310&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84905057310&partnerID=8YFLogxK

U2 - 10.1124/jpet.114.214437

DO - 10.1124/jpet.114.214437

M3 - Article

C2 - 24947466

AN - SCOPUS:84905057310

VL - 350

SP - 495

EP - 505

JO - Journal of Pharmacology and Experimental Therapeutics

JF - Journal of Pharmacology and Experimental Therapeutics

SN - 0022-3565

IS - 3

ER -