mGluR5 Antagonist-Induced Psychoactive Properties: MTEP Drug Discrimination, a Pharmacologically Selective Non–NMDA Effect with Apparent Lack of Reinforcing Properties

@article{Swedberg2014mGluR5AP,
  title={mGluR5 Antagonist-Induced Psychoactive Properties: MTEP Drug Discrimination, a Pharmacologically Selective Non–NMDA Effect with Apparent Lack of Reinforcing Properties},
  author={Michael D B Swedberg and Maria Ellgren and Patrick Raboisson},
  journal={The Journal of Pharmacology and Experimental Therapeutics},
  year={2014},
  volume={349},
  pages={155 - 164}
}
Fenobam [N-(3-chlorophenyl)-N′-(4,5-dihydro-1-methyl-4-oxo-1H-imidazole-2-yl)urea], a potent metabotropic glutamate mGluR5 receptor antagonist, reported to have analgesic effects in animals and anxiolytic effects in humans, also caused adverse events, including psychostimulant-type effects and “derealization phenomena.” Recent electrophysiologic, pharmacologic, and anatomic data show that the mGluR5 antagonists 2-methyl-6-(phenylethynyl)pyridine (MPEP) and (E)-2-methyl-6-styryl-pyridine (SIB… 

Figures and Tables from this paper

MTEP, a Selective mGluR5 Antagonist, Had a Neuroprotective Effect but Did Not Prevent the Development of Spontaneous Recurrent Seizures and Behavioral Comorbidities in the Rat Lithium–Pilocarpine Model of Epilepsy

TLDR
It is found that the administration of MTEP during the latent phase of the model did not improve survival, prevent the development of epilepsy, or attenuate its manifestations in rats, however, MTEP treatment completely prevented neuronal loss and partially attenuated astrogliosis in the hippocampus.

Partial mGlu5 Negative Allosteric Modulators Attenuate Cocaine-Mediated Behaviors and Lack Psychotomimetic-Like Effects

TLDR
The present data suggest that partial mGlu5 NAM activity is sufficient to produce therapeutic effects similar to full mGlam glutamate receptor 5 NAMs, but with a broader therapeutic index.

Pharmacology of Basimglurant ( RO 4917523 , RG 7090 ) , a Unique Metabotropic Glutamate Receptor 5 Negative Allosteric Modulator in Clinical Development for Depression s

TLDR
Basimglurant has favorable drug-like properties, a differentiated molecularmechanism of action, and antidepressant-like features that suggest the possibility of also addressing important comorbidities of MDD including anxiety and pain as well as daytime sleepiness and apathy or lethargy.

Pharmacology of Basimglurant (RO4917523, RG7090), a Unique Metabotropic Glutamate Receptor 5 Negative Allosteric Modulator in Clinical Development for Depression

TLDR
Basimglurant has favorable drug-like properties, a differentiated molecular mechanism of action, and antidepressant-like features that suggest the possibility of also addressing important comorbidities of MDD including anxiety and pain as well as daytime sleepiness and apathy or lethargy.

Metabotropic Glutamate Receptors As Emerging Targets for the Treatment of Schizophrenia

TLDR
Emerging preclinical and clinical literature suggests that pharmacological targeting of metabotropic glutamate receptors could potentially provide an alternative approach for designing safer and more efficacious therapeutics for treating schizophrenia.

Drug discrimination: A versatile tool for characterization of CNS safety pharmacology and potential for drug abuse.

Emerging Trends in Pain Modulation by Metabotropic Glutamate Receptors

TLDR
The role of mGluRs in acute and persistent pain processing and emerging pharmacotherapies for pain management is addressed, supporting glutamate receptors as promising potential targets for pain relieving drug development.

References

SHOWING 1-10 OF 76 REFERENCES

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

TLDR
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 receptors antagonists in the modulation of mood disorders.

The Metabotropic Glutamate Receptor Subtype 5 Antagonist Fenobam Is Analgesic and Has Improved in Vivo Selectivity Compared with the Prototypical Antagonist 2-Methyl-6-(phenylethynyl)-pyridine

TLDR
It is shown that fenobam reduces formalin-induced pain behaviors and relieves established inflammation-induced thermal hypersensitivity in mice and has an improved in vivo selectivity for mGlu5 over MPEP.

Fenobam: A Clinically Validated Nonbenzodiazepine Anxiolytic Is a Potent, Selective, and Noncompetitive mGlu5 Receptor Antagonist with Inverse Agonist Activity

TLDR
The non-GABAergic activity of fenobam, coupled with its robust anxiolytic activity and reported efficacy in human in a double blind placebo-controlled trial, supports the potential of developing mGlu5 receptor antagonists with an improved therapeutic window over benzodiazepines as novel anxIOlytic agents.

The phencyclidine-like discriminative stimulus effects and reinforcing properties of the NR2B-selective N-methyl-D-aspartate antagonist CP-101 606 in rats and rhesus monkeys

TLDR
The data show that NR2B subunit containing NMDA receptors plays a role in the production of the subjective effects and abuse potential associated with many subtype-nonselective NMDA receptor antagonists such as PCP, and suggests that CP-101 606 has some PCP-like discriminative stimulus effects in rats and monkeys and functions as a positive reinforcer in monkeys.

Attenuation of Behavioral Effects of Cocaine by the Metabotropic Glutamate Receptor 5 Antagonist 2-Methyl-6-(phenylethynyl)-pyridine in Squirrel Monkeys: Comparison with Dizocilpine

TLDR
The findings point to a significant contribution of mGluR5 mechanisms in the behavioral effects of cocaine related to its abuse and suggest that MPEP has properties of a functional cocaine antagonist, which are not secondary to antagonism at NMDA receptors.

Anticonvulsant, anxiolytic and discriminative effects of the AMPA antagonist 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo(f)quinoxaline (NBQX).

TLDR
It is demonstrated that NBQX has anticonvulsant effects, has limited anxiolytic effects, and does not produce subjective effects of PCP or opiate type.

mGluR5 antagonists 2-methyl-6-(phenylethynyl)-pyridine and (E)-2-methyl-6-(2-phenylethenyl)-pyridine reduce traumatic neuronal injury in vitro and in vivo by antagonizing N-methyl-D-aspartate receptors.

TLDR
Data suggest that MPEP and SIB-1893 may have therapeutic potential in brain injury, although the mechanisms of neuroprotective action for these drugs may reflect their ability to modulate NMDA receptor activity.

N-Methyl-D-Aspartate Antagonists and Drug Discrimination

TLDR
Although many instances of intermediate responding in DD can be explained by low efficacy at the receptors that mediate the DS effects of the training drug, certain outcomes produced by PCP-type drugs do not offer valid measures of efficacy, and require more detailed behavioral analyzes.
...