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The behavioral profile of the potent and selective mGlu5 receptor antagonist 3-[(2-methyl-1,3-thiazol-4-yl)ethynyl]pyridine (MTEP) in rodent models of anxiety.
Neuropsychopharmacology. 2004 Nov; 29(11):1971-9.N

Abstract

Previous reports have demonstrated the anxiolytic effect of the potent and systemically active metabotropic glutamate subtype 5 (mGlu5) receptor antagonist 2-methyl-6-(phenylethynyl)pyridine (MPEP) in rodents. Here, we present evidence for the anxiolytic activity of a novel mGlu5 receptor antagonist, 3-[(2-methyl-1,3-thiazol-4-yl)ethynyl]pyridine (MTEP), in rats and compare its profile to the benzodiazepine receptor agonist diazepam. MTEP occupied mGlu5 receptors in a dose-dependent manner with essentially full receptor occupancy at the highest dose tested (10 mg/kg, i.p.). At doses appropriate for mGlu5 receptor-mediated effects, MTEP significantly reduced fear-potentiated startle and increased punished responding in a modified Geller-Seifter conflict model consistent with an anxiolytic-like profile. In both models, the magnitude of the anxiolytic-like response was similar to that seen with diazepam. In contrast, MTEP decreased unpunished responding to a lesser extent than diazepam and had no effect on rotarod performance when administered either alone or in combination with ethanol. Repeated dosing with MTEP in this model eliminated the increase in punished responding observed with acute dosing. The present results suggest that mGlu5 receptor antagonists lack the side effects seen with benzodiazepines, such as sedation and ethanol interaction, and provide insight into a possible role for mGlu5 receptor antagonists in the modulation of mood disorders.

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Authors+Show Affiliations

Busse CS
Merck Research Laboratories, San Diego, CA, USA. Christopher_busse@merck.com
Brodkin J
No affiliation info available
Tattersall D
No affiliation info available
Anderson JJ
No affiliation info available
Warren N
No affiliation info available
Tehrani L
No affiliation info available
Bristow LJ
No affiliation info available
Varney MA
No affiliation info available
Cosford ND
No affiliation info available

MeSH

AnimalsAnxietyDisease Models, AnimalDose-Response Relationship, DrugMaleMicePyridinesRatsRats, Sprague-DawleyRats, WistarReceptor, Metabotropic Glutamate 5Receptors, Metabotropic GlutamateThiazoles

Pub Type(s)

Comparative Study
Journal Article

Language

eng

PubMed ID

15305166

Citation

Busse, Chris S., et al. "The Behavioral Profile of the Potent and Selective mGlu5 Receptor Antagonist 3-[(2-methyl-1,3-thiazol-4-yl)ethynyl]pyridine (MTEP) in Rodent Models of Anxiety." Neuropsychopharmacology : Official Publication of the American College of Neuropsychopharmacology, vol. 29, no. 11, 2004, pp. 1971-9.
Busse CS, Brodkin J, Tattersall D, et al. The behavioral profile of the potent and selective mGlu5 receptor antagonist 3-[(2-methyl-1,3-thiazol-4-yl)ethynyl]pyridine (MTEP) in rodent models of anxiety. Neuropsychopharmacology. 2004;29(11):1971-9.
Busse, C. S., Brodkin, J., Tattersall, D., Anderson, J. J., Warren, N., Tehrani, L., Bristow, L. J., Varney, M. A., & Cosford, N. D. (2004). The behavioral profile of the potent and selective mGlu5 receptor antagonist 3-[(2-methyl-1,3-thiazol-4-yl)ethynyl]pyridine (MTEP) in rodent models of anxiety. Neuropsychopharmacology : Official Publication of the American College of Neuropsychopharmacology, 29(11), 1971-9.
Busse CS, et al. The Behavioral Profile of the Potent and Selective mGlu5 Receptor Antagonist 3-[(2-methyl-1,3-thiazol-4-yl)ethynyl]pyridine (MTEP) in Rodent Models of Anxiety. Neuropsychopharmacology. 2004;29(11):1971-9. PubMed PMID: 15305166.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - The behavioral profile of the potent and selective mGlu5 receptor antagonist 3-[(2-methyl-1,3-thiazol-4-yl)ethynyl]pyridine (MTEP) in rodent models of anxiety. AU - Busse,Chris S, AU - Brodkin,Jesse, AU - Tattersall,David, AU - Anderson,Jeffery J, AU - Warren,Noelle, AU - Tehrani,Lida, AU - Bristow,Linda J, AU - Varney,Mark A, AU - Cosford,Nicholas D P, PY - 2004/8/12/pubmed PY - 2005/1/12/medline PY - 2004/8/12/entrez SP - 1971 EP - 9 JF - Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology JO - Neuropsychopharmacology VL - 29 IS - 11 N2 - Previous reports have demonstrated the anxiolytic effect of the potent and systemically active metabotropic glutamate subtype 5 (mGlu5) receptor antagonist 2-methyl-6-(phenylethynyl)pyridine (MPEP) in rodents. Here, we present evidence for the anxiolytic activity of a novel mGlu5 receptor antagonist, 3-[(2-methyl-1,3-thiazol-4-yl)ethynyl]pyridine (MTEP), in rats and compare its profile to the benzodiazepine receptor agonist diazepam. MTEP occupied mGlu5 receptors in a dose-dependent manner with essentially full receptor occupancy at the highest dose tested (10 mg/kg, i.p.). At doses appropriate for mGlu5 receptor-mediated effects, MTEP significantly reduced fear-potentiated startle and increased punished responding in a modified Geller-Seifter conflict model consistent with an anxiolytic-like profile. In both models, the magnitude of the anxiolytic-like response was similar to that seen with diazepam. In contrast, MTEP decreased unpunished responding to a lesser extent than diazepam and had no effect on rotarod performance when administered either alone or in combination with ethanol. Repeated dosing with MTEP in this model eliminated the increase in punished responding observed with acute dosing. The present results suggest that mGlu5 receptor antagonists lack the side effects seen with benzodiazepines, such as sedation and ethanol interaction, and provide insight into a possible role for mGlu5 receptor antagonists in the modulation of mood disorders. SN - 0893-133X UR - https://www.unboundmedicine.com/medline/citation/15305166/The_behavioral_profile_of_the_potent_and_selective_mGlu5_receptor_antagonist_3_[_2_methyl_13_thiazol_4_yl_ethynyl]pyridine__MTEP__in_rodent_models_of_anxiety_ L2 - https://doi.org/10.1038/sj.npp.1300540 DB - PRIME DP - Unbound Medicine ER -