17 research outputs found
A Novel Class of Succinimide-Derived Negative Allosteric Modulators of Metabotropic Glutamate Receptor Subtype 1 Provides Insight into a Disconnect in Activity between the Rat and Human Receptors
Recent
progress in the discovery of mGlu<sub>1</sub> allosteric
modulators has suggested the modulation of mGlu<sub>1</sub> could
offer possible treatment for a number of central nervous system disorders;
however, the available chemotypes are inadequate to fully investigate
the therapeutic potential of mGlu<sub>1</sub> modulation. To address
this issue, we used a fluorescence-based high-throughput screening
assay to screen an allosteric modulator-biased library of compounds
to generate structurally diverse mGlu<sub>1</sub> negative allosteric
modulator hits for chemical optimization. Herein, we describe the
discovery and characterization of a novel mGlu<sub>1</sub> chemotype.
This series of succinimide negative allosteric modulators, exemplified
by VU0410425, exhibited potent inhibitory activity at rat mGlu<sub>1</sub> but was, surprisingly, inactive at human mGlu<sub>1</sub>. VU0410425 and a set of chemically diverse mGlu<sub>1</sub> negative
allosteric modulators previously reported in the literature were utilized
to examine this species disconnect between rat and human mGlu<sub>1</sub> activity. Mutation of the key transmembrane domain residue
757 and functional screening of VU0410425 and the literature compounds
suggests that amino acid 757 plays a role in the activity of these
compounds, but the contribution of the residue is scaffold specific,
ranging from critical to minor. The operational model of allosterism
was used to estimate the binding affinities of each compound to compare
to functional data. This novel series of mGlu<sub>1</sub> negative
allosteric modulators provides valuable insight into the pharmacology
underlying the disconnect between rat and human mGlu<sub>1</sub> activity,
an issue that must be understood to progress the therapeutic potential
of allosteric modulators of mGlu<sub>1</sub>
Discovery of molecular switches within the ADX-47273 mGlu5 PAM scaffold that modulate modes of pharmacology to afford potent mGlu5 NAMs, PAMs and partial antagonists
Substituted 1‑Phenyl-3-(pyridin-2-yl)urea Negative Allosteric Modulators of mGlu<sub>5</sub>: Discovery of a New Tool Compound VU0463841 with Activity in Rat Models of Cocaine Addiction
Cocaine
is a powerful and highly addictive stimulant that disrupts the normal
reward circuitry in the central nervous system (CNS), producing euphoric
effects. Cocaine use can lead to acute and life threatening emergencies,
and abuse is associated with increased risk for contracting infectious
diseases. Though certain types of behavioral therapy have proven effective
for treatment of cocaine addiction, relapse remains high, and there
are currently no approved medications for the treatment of cocaine
abuse. Evidence has continued to accumulate that indicates a critical
role for the metabotropic glutamate receptor subtype 5 (mGlu<sub>5</sub>) in the modulation of neural circuitry associated with the addictive
properties of cocaine. While the small molecule mGlu<sub>5</sub> negative
allosteric modulator (NAM) field is relatively advanced, investigation
into the potential of small molecule mGlu<sub>5</sub> NAMs for the
treatment of cocaine addiction remains an area of high interest. Herein
we describe the discovery and characterization of a potent and selective
compound <b>29</b> (VU0463841) with good CNS exposure in rats.
The utility of <b>29</b> (VU0463841) was demonstrated by its
ability to attenuate drug seeking behaviors in relevant rat models
of cocaine addiction
Chemical Modulation of Mutant mGlu<sub>1</sub> Receptors Derived from Deleterious <i>GRM1</i> Mutations Found in Schizophrenics
Schizophrenia is a complex and highly
heterogeneous psychiatric
disorder whose precise etiology remains elusive. While genome-wide
association studies (GWAS) have identified risk genes, they have failed
to determine if rare coding single nucleotide polymorphisms (nsSNPs)
contribute in schizophrenia. Recently, two independent studies identified
12 rare, deleterious nsSNPS in the <i>GRM1</i> gene, which
encodes the metabotropic glutamate receptor subtype 1 (mGlu<sub>1</sub>), in schizophrenic patients. Here, we generated stable cell lines
expressing the mGlu<sub>1</sub> mutant receptors and assessed their
pharmacology. Using both the endogenous agonist glutamate and the
synthetic agonist DHPG, we found that several of the mutant mGlu<sub>1</sub> receptors displayed a loss of function that was not due to
a loss in plasma membrane expression. Due to a lack of mGlu<sub>1</sub> positive allosteric modulators (PAM) tool compounds active at human
mGlu<sub>1</sub>, we optimized a known mGlu<sub>4</sub> PAM/mGlu<sub>1</sub> NAM chemotype into a series of potent and selective mGlu<sub>1</sub> PAMs by virtue of a double “molecular switch”.
Employing mGlu<sub>1</sub> PAMs from multiple chemotypes, we demonstrate
that the mutant receptors can be potentiated by small molecules and
in some cases efficacy restored to that comparable to wild type mGlu<sub>1</sub> receptors, suggesting deficits in patients with schizophrenia
due to these mutations may be amenable to intervention with an mGlu<sub>1</sub> PAM. However, in wild type animals, mGlu<sub>1</sub> negative
allosteric modulators (NAMs) are efficacious in classic models predictive
of antipsychotic activity, whereas we show that mGlu<sub>1</sub> PAMs
have no effect to slight potentiation in these models. These data
further highlight the heterogeneity of schizophrenia and the critical
role of patient selection strategies in psychiatric clinical trials
to match genotype with therapeutic mechanism
Design of 4-Oxo-1-aryl-1,4-dihydroquinoline-3-carboxamides as Selective Negative Allosteric Modulators of Metabotropic Glutamate Receptor Subtype 2
Discovery of a Selective and CNS Penetrant Negative Allosteric Modulator of Metabotropic Glutamate Receptor Subtype 3 with Antidepressant and Anxiolytic Activity in Rodents
Design of 4‑Oxo-1-aryl-1,4-dihydroquinoline-3-carboxamides as Selective Negative Allosteric Modulators of Metabotropic Glutamate Receptor Subtype 2
Both
orthosteric and allosteric antagonists of the group II metabotropic
glutamate receptors (mGlus) have been used to establish a link between
mGlu<sub>2/3</sub> inhibition and a variety of CNS diseases and disorders.
Though these tools typically have good selectivity for mGlu<sub>2/3</sub> versus the remaining six members of the mGlu family, compounds that
are selective for only one of the individual group II mGlus have proved
elusive. Herein we report on the discovery of a potent and highly
selective mGlu<sub>2</sub> negative allosteric modulator <b>58</b> (VU6001192) from a series of 4-oxo-1-aryl-1,4-dihydroquinoline-3-carboxamides.
The concept for the design of this series centered on morphing a quinoline
series recently disclosed in the patent literature into a chemotype
previously used for the preparation of muscarinic acetylcholine receptor
subtype 1 positive allosteric modulators. Compound <b>58</b> exhibits a favorable profile and will be a useful tool for understanding
the biological implications of selective inhibition of mGlu<sub>2</sub> in the CNS
The Role of Aldehyde Oxidase and Xanthine Oxidase in the Biotransformation of a Novel Negative Allosteric Modulator of Metabotropic Glutamate Receptor Subtype 5
Discovery of a Selective and CNS Penetrant Negative Allosteric Modulator of Metabotropic Glutamate Receptor Subtype 3 with Antidepressant and Anxiolytic Activity in Rodents
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
(mGlu<sub>2</sub> and mGlu<sub>3</sub>) 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 mGlu<sub>3</sub> NAM <b>106</b> (VU0650786) suitable for in vivo work. Compound <b>106</b> is a member of a series of 5-aryl-6,7-dihydropyrazoloÂ[1,5-<i>a</i>]Âpyrazine-4Â(5<i>H</i>)-one compounds originally
identified as a mGlu<sub>5</sub> 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 <b>106</b> represent
the first examples in which an mGlu<sub>3</sub> NAM has demonstrated
efficacy in models where prior efficacy had previously been noted
with nonselective group II antagonists