Discovery of VU0409106: A negative allosteric modulator of mGlu5 with activity in a mouse model of anxiety

Felts, Andrew S.; Rodriguez, Alice L.; Morrison, Ryan D.; Venable, Daryl F.; Manka, Jason; Bates, Brittney S.; Blobaum, Anna L.; Byers, Frank W.; Daniels, J. Scott; Niswender, Colleen M.; Jones, Carrie K.; Conn, P. Jeffrey; Lindsley, Craig W.; Emmitte, Kyle A.

doi:10.1016/j.bmcl.2013.09.001

Cited by 28 publications

(43 citation statements)

References 67 publications

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“…66 Likewise, this behavior has proven sensitive to a variety of mGlu 5 NAM compounds from diverse chemotypes. 38,67,68 As such, the marble burying assay has often been used as a convenient method for assessing anxiolytic activity. It is worth noting that recent reports have argued that the assay reflects a repetitive and perseverative behavior such as OCD as opposed to novelty-induced anxiety.…”

Section: Resultsmentioning

confidence: 99%

Discovery of a Selective and CNS Penetrant Negative Allosteric Modulator of Metabotropic Glutamate Receptor Subtype 3 with Antidepressant and Anxiolytic Activity in Rodents

et al. 2015

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Previous preclinical work has demonstrated the therapeutic potential of antagonists of the group II metabotropic glutamate receptors (mGlus). Still, compounds that are selective for the individual group II mGlus (mGlu2 and mGlu3) have been scarce. There remains a need for such compounds with the balance of properties suitable for convenient use in a wide array of rodent behavioral studies. We describe here the discovery of a selective mGlu3 NAM 106 (VU0650786) suitable for in vivo work. Compound 106 is a member of a series of 5-aryl-6,7-dihydropyrazolo[1,5-a]pyrazine-4(5H)-one compounds originally identified as a mGlu5 positive allosteric modulator (PAM) chemotype. Its suitability for use in rodent behavioral models has been established by extensive in vivo PK studies, and the behavioral experiments presented here with compound 106 represent the first examples in which an mGlu3 NAM has demonstrated efficacy in models where prior efficacy had previously been noted with nonselective group II antagonists.

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Section: Resultsmentioning

confidence: 99%

Discovery of a Selective and CNS Penetrant Negative Allosteric Modulator of Metabotropic Glutamate Receptor Subtype 3 with Antidepressant and Anxiolytic Activity in Rodents

et al. 2015

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“…Another possible explanation is that the psychotomimetic effects of full mGlu 5 NAMs are associated with inverse agonist activity (Gasparini et al, 1999;Porter et al, 2005). Although multiple reports demonstrate potential for novel mGlu 5 NAMs to reduce cocaine self-administration as well as antidepressant-and anxiolyticlike activity (Keck et al, 2012(Keck et al, , 2014Amato et al, 2013;Felts et al, 2013;Hughes et al, 2013;Rook et al, 2015), a remaining challenge includes developing compounds with a substantial therapeutic window.…”

Section: Introductionmentioning

confidence: 99%

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

Gould

Amato

Bubser

et al. 2015

Neuropsychopharmacol

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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.

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“…In addition to evaluating the in vivo efficacy/occupancy relationship of closely related members of the biaryl acetylenic mGlu 5 allosteric modulator series, we also evaluated the effects of a novel mGlu 5 NAM, VU0409106 (Felts et al, 2013). This mGlu 5 NAM bears no structural resemblance to FPEB and the other mGlu 5 modulators studied (Figure 1).…”

Section: In Vivo Ro/efficacy Relationship Of Mglu 5 Pamsmentioning

confidence: 99%

Relationship between In Vivo Receptor Occupancy and Efficacy of Metabotropic Glutamate Receptor Subtype 5 Allosteric Modulators with Different In Vitro Binding Profiles

Rook

Tantawy

Ansari

et al. 2014

Neuropsychopharmacol

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Allosteric modulators of the metabotropic glutamate receptor subtype 5 (mGlu 5 ) have exciting potential as therapeutic agents for multiple brain disorders. Translational studies with mGlu 5 modulators have relied on mGlu 5 allosteric site positron emission tomography (PET) radioligands to assess receptor occupancy in the brain. However, recent structural and modeling studies suggest that closely related mGlu 5 allosteric modulators can bind to overlapping but not identical sites, which could complicate interpretation of in vivo occupancy data, even when PET ligands and drug leads are developed from the same chemical scaffold. We now report that systemic administration of the novel mGlu 5 positive allosteric modulator VU0092273 displaced the structurally related mGlu 5 PET ligand, [ 18 F]FPEB, with measures of in vivo occupancy that closely aligned with its in vivo efficacy. In contrast, a close analog of VU0092273 and [ 18 F]FPEB, VU0360172, provided robust efficacy in rodent models in the absence of detectable occupancy. Furthermore, a structurally unrelated mGlu 5 negative allosteric modulator, VU0409106, displayed measures of in vivo occupancy that correlated well with behavioral effects, despite the fact that VU0409106 is structurally unrelated to [18 F]FPEB. Interestingly, all three compounds inhibit radioligand binding to the prototypical MPEP/FPEB allosteric site in vitro. However, VU0092273 and VU0409106 bind to this site in a fully competitive manner, whereas the interaction of VU0360172 is noncompetitive. Thus, while close structural similarity between PET ligands and drug leads does not circumvent issues associated with differential binding to a given target, detailed molecular pharmacology analysis accurately predicts utility of ligand pairs for in vivo occupancy studies.

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Discovery of VU0409106: A negative allosteric modulator of mGlu5 with activity in a mouse model of anxiety

Cited by 28 publications

References 67 publications

Discovery of a Selective and CNS Penetrant Negative Allosteric Modulator of Metabotropic Glutamate Receptor Subtype 3 with Antidepressant and Anxiolytic Activity in Rodents

Discovery of a Selective and CNS Penetrant Negative Allosteric Modulator of Metabotropic Glutamate Receptor Subtype 3 with Antidepressant and Anxiolytic Activity in Rodents

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

Relationship between In Vivo Receptor Occupancy and Efficacy of Metabotropic Glutamate Receptor Subtype 5 Allosteric Modulators with Different In Vitro Binding Profiles

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