Search tips
Search criteria

Results 1-7 (7)

Clipboard (0)

Select a Filter Below

Year of Publication
Document Types
1.  Selective Actions of Novel Allosteric Modulators Reveal Functional Heteromers of Metabotropic Glutamate Receptors in the CNS 
The Journal of Neuroscience  2014;34(1):79-94.
Metabotropic glutamate (mGlu) receptors play important roles in regulating CNS function and are known to function as obligatory dimers. Although recent studies have suggested heterodimeric assembly of mGlu receptors in vitro, the demonstration that distinct mGlu receptor proteins can form heterodimers or hetero-complexes with other mGlu subunits in native tissues, such as neurons, has not been shown. Using biochemical and pharmacological approaches, we demonstrate here that mGlu2 and mGlu4 form a hetero-complex in native rat and mouse tissues which exhibits a distinct pharmacological profile. These data greatly extend our current understanding of mGlu receptor interaction and function and provide compelling evidence that mGlu receptors can function as heteromers in intact brain circuits.
PMCID: PMC3866496  PMID: 24381270
2.  Functional selectivity induced by mGlu4 receptor positive allosteric modulation and concomitant activation of Gq coupled receptors 
Neuropharmacology  2012;66:122-132.
Metabotropic glutamate receptors (mGlus) are a group of Family C Seven Transmembrane Spanning Receptors (7TMRs) that play important roles in modulating signaling transduction, particularly within the central nervous system. mGlu4 belongs to a subfamily of mGlus that is predominantly coupled to Gi/o G proteins. We now report that the ubiquitous autacoid and neuromodulator, histamine, induces substantial glutamate-activated calcium mobilization in mGlu4-expressing cells, an effect which is observed in the absence of co-expressed chimeric G proteins. This strong induction of calcium signaling downstream of glutamate activation of mGlu4 depends upon the presence of H1 histamine receptors. Interestingly, the potentiating effect of histamine activation does not extend to other mGlu4-mediated signaling events downstream of Gi/o G proteins, such as cAMP inhibition, suggesting that the presence of Gq coupled receptors such as H1 may bias normal mGlu4-mediated Gi/o signaling events. When the activity induced by small molecule positive allosteric modulators of mGlu4 is assessed, the potentiated signaling of mGlu4 is further biased by histamine toward calcium-dependent pathways. These results suggest that Gi/o-coupled mGlus may induce substantial, and potentially unexpected, calcium-mediated signaling events if stimulation occurs concomitantly with activation of Gq receptors. Additionally, our results suggest that signaling induced by small molecule positive allosteric modulators may be substantially biased when Gq receptors are co-activated.
This article is part of a Special Issue entitled ‘mGluR’
PMCID: PMC3412075  PMID: 22426233
Glutamate; Histamine; Receptor; Allosteric modulator; Functional selectivity
3.  Synthesis and SAR of a novel metabotropic glutamate receptor 4 (mGlu4) antagonist: Unexpected ‘molecular switch’ from a closely related mGlu4 positive allosteric modulator 
Herein we report the discovery and SAR of a novel antagonist of metabotropic glutamate receptor 4 (mGlu4). The antagonist was discovered via a molecular switch from a closely related mGlu4 positive allosteric modulator (PAM). This antagonist (VU0448383) displays an IC50 value of 8.2 ± 0.4 μM and inhibits an EC80 glutamate response by 63.1 ± 6.6%.
PMCID: PMC3319082  PMID: 22030026
Metabotropic glutamate receptor 4; mGlu4; Molecular switch; Antagonist
4.  Discovery, Synthesis, SAR Development of a Series of N-4-(2,5-dioxopyrrolidin-1-yl)-phenylpicolinamides (VU0400195, ML182): Characterization of a Novel Positive Allosteric Modulator of the Metabotropic Glutamate Receptor 4 (mGlu4) with Oral Efficacy in an anti-Parkinsonian Animal Model 
Journal of medicinal chemistry  2011;54(21):7639-7647.
There is an increasing amount of literature data showing the positive effects on preclinical anti-Parkinsonian rodent models with selective positive allosteric modulators of metabotropic glutamate receptor 4 (mGlu4).1 However, most of the data generated utilize compounds that have not been optimized for drug-like properties and, as a consequence, they exhibit poor pharmacokinetic properties and thus do not cross the blood-brain barrier. Herein, we report on a series of N-4-(2,5-dioxopyrrolidin-1-yl)-phenylpicolinamides with improved PK properties with excellent potency and selectivity as well as improved brain exposure in rodents. Finally, ML182 was shown to be orally active in the haloperidol induced catalepsy model, a well-established anti-Parkinsonian model.
PMCID: PMC3226828  PMID: 21966889
metabotropic glutamate receptors; mGlu4; positive allosteric modulators; Parkinson’s disease; haloperidol-induced catalepsy; structure-activity relationship (SAR); oral efficacy; brain penetration
5.  Solution-Phase Parallel Synthesis and SAR of Homopiperazinyl Analogs as Positive Allosteric Modulators of mGlu4 
ACS combinatorial science  2011;13(2):159-165.
Using a functional high-throughput screening (HTS) and subsequent solution-phase parallel synthesis approach, we have discovered a novel series of positive allosteric modulators for mGlu4, a G-protein coupled receptor. This series is comprised of a homopiperazine central core. The solution-phase parallel synthesis and SAR of analogs derived from this series will be presented. This series of positive allosteric modulators of mGlu4 provide critical research tools to further probe the mGlu4-mediated effects in Parkinson’s disease.
PMCID: PMC3057427  PMID: 21338051
6.  Discovery, Synthesis, and Structure Activity Relationship Development of a Series of N-(4-acetamido)phenylpicolinamides as Positive Allosteric Modulators of Metabotropic Glutamate Receptor 4 (mGlu4) with CNS Exposure in Rats 
Journal of medicinal chemistry  2011;54(4):1106-1110.
Herein we report the discovery, synthesis and evaluation of a series of N-(4-acetamido)-phenylpicolinamides as positive allosteric modulators of mGlu4.a Compounds from the series show submicromolar potency at both human and rat mGlu4. In addition, pharmacokinetic studies utilizing subcutaneous dosing demonstrated good brain exposure in rats.
PMCID: PMC3166797  PMID: 21247167
7.  Synthesis and Evaluation of a Series of Heterobiaryl Amides that are Centrally Penetrant Metabotropic Glutamate Receptor 4 (mGluR4) Positive Allosteric Modulators (PAMs) 
Journal of medicinal chemistry  2009;52(14):4115-4118.
We report the synthesis and evaluation of a series of heterobiaryl amides as positive allosteric modulators of mGluR4. Compounds 9b and 9c showed submicromolar potency at both human and rat mGluR4. In addition, both 9b and 9c were shown to be centrally penetrant in rats using nontoxic vehicles, a major advance for the mGluR4 field.
PMCID: PMC2765192  PMID: 19469556

Results 1-7 (7)