In vivo receptor occupancy of mGlu5 receptor antagonists using the novel radioligand [3H]3-methoxy-5-(pyridin-2-ylethynyl)pyridine)

156

112

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.

Section: Discussionmentioning

confidence: 94%

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

Busse

Brodkin

Tattersall

et al. 2004

156

112

“…These results strengthen the idea of combining different antidepressant treatments to maximize therapeutic efficacy (Connolly and Thase, 2011;Palaniyappan et al, 2009). Indeed, CTEP may serve as a basis for future antidepressants that specifically target the glutamate system, as its pharmacokinetic properties are significantly improved from previous mGluR5 antagonists such as MPEP and MTEP (Lindemann et al, 2011;Anderson et al, 2003;Busse et al, 2004).…”

Section: Discussionmentioning

confidence: 99%

Homer1/mGluR5 Activity Moderates Vulnerability to Chronic Social Stress

Wagner

Hartmann

Labermaier

et al. 2014

Stress-induced psychiatric disorders, such as depression, have recently been linked to changes in glutamate transmission in the central nervous system. Glutamate signaling is mediated by a range of receptors, including metabotropic glutamate receptors (mGluRs). In particular, mGluR subtype 5 (mGluR5) is highly implicated in stress-induced psychopathology. The major scaffold protein Homer1 critically interacts with mGluR5 and has also been linked to several psychopathologies. Yet, the specific role of Homer1 in this context remains poorly understood. We used chronic social defeat stress as an established animal model of depression and investigated changes in transcription of Homer1a and Homer1b/c isoforms and functional coupling of Homer1 to mGluR5. Next, we investigated the consequences of Homer1 deletion, overexpression of Homer1a, and chronic administration of the mGluR5 inverse agonist CTEP (2-chloro-4-((2,5-dimethyl-1-(4-(trifluoromethoxy)phenyl)-1H-imidazol-4-yl)ethynyl)pyridine) on the effects of chronic stress. In mice exposed to chronic stress, Homer1b/c, but not Homer1a, mRNA was upregulated and, accordingly, Homer1/mGluR5 coupling was disrupted. We found a marked hyperactivity behavior as well as a dysregulated hypothalamic-pituitary-adrenal axis activity in chronically stressed Homer1 knockout (KO) mice. Chronic administration of the selective and orally bioavailable mGluR5 inverse agonist, CTEP, was able to recover behavioral alterations induced by chronic stress, whereas overexpression of Homer1a in the hippocampus led to an increased vulnerability to chronic stress, reflected in an increased physiological response to stress as well as enhanced depression-like behavior. Overall, our results implicate the glutamatergic system in the emergence of stress-induced psychiatric disorders, and support the Homer1/mGluR5 complex as a target for the development of novel antidepressant agents.

“…In vivo occupancy studies were conducted to provide a direct comparison between central mGlu 5 occupancy and behavioral effects utilizing the method of Anderson et al (2003). Briefly, animals were dosed with M-5MPEP (1.8-56.6 mg/kg), Br-5MPEPy (3-56.6 mg/kg) or MTEP (0.3-50 mg/kg).…”

Section: Occupancymentioning

confidence: 99%

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

Gould

Amato

Bubser

et al. 2015

Cocaine abuse remains a public health concern for which pharmacotherapies are largely ineffective. Comorbidities between cocaine abuse, depression, and anxiety support the development of novel treatments targeting multiple symptom clusters. Selective negative allosteric modulators (NAMs) targeting the metabotropic glutamate receptor 5 (mGlu 5 ) subtype are currently in clinical trials for the treatment of multiple neuropsychiatric disorders and have shown promise in preclinical models of substance abuse. However, complete blockade or inverse agonist activity by some full mGlu 5 NAM chemotypes demonstrated adverse effects, including psychosis in humans and psychotomimetic-like effects in animals, suggesting a narrow therapeutic window. Development of partial mGlu 5 NAMs, characterized by their submaximal but saturable levels of blockade, may represent a novel approach to broaden the therapeutic window. To understand potential therapeutic vs adverse effects in preclinical behavioral assays, we examined the partial mGlu 5 NAMs, M-5MPEP and Br-5MPEPy, in comparison with the full mGlu 5 NAM MTEP across models of addiction and psychotomimetic-like activity. M-5MPEP, Br-5MPEPy, and MTEP dose-dependently decreased cocaine self-administration and attenuated the discriminative stimulus effects of cocaine. M-5MPEP and Br-5MPEPy also demonstrated antidepressant-and anxiolytic-like activity. Dose-dependent effects of partial and full mGlu 5 NAMs in these assays corresponded with increasing in vivo mGlu 5 occupancy, demonstrating an orderly occupancy-to-efficacy relationship. PCP-induced hyperlocomotion was potentiated by MTEP, but not by M-5MPEP and Br-5MPEPy. Further, MTEP, but not M-5MPEP, potentiated the discriminative-stimulus effects of PCP. The present data suggest that partial mGlu 5 NAM activity is sufficient to produce therapeutic effects similar to full mGlu 5 NAMs, but with a broader therapeutic index.