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.

PubWeight™: 1.21‹?› | Rank: Top 10%

🔗 View Article (PMC 3179182)

Published in Bioorg Med Chem Lett on December 03, 2010

Authors

Jeffrey P Lamb1, Darren W Engers, Colleen M Niswender, Alice L Rodriguez, Daryl F Venable, P Jeffrey Conn, Craig W Lindsley

Author Affiliations

1: Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232, USA.

Articles citing this

Itraconazole and arsenic trioxide inhibit Hedgehog pathway activation and tumor growth associated with acquired resistance to smoothened antagonists. Cancer Cell (2013) 2.62

Allosteric modulation of seven transmembrane spanning receptors: theory, practice, and opportunities for central nervous system drug discovery. J Med Chem (2012) 2.10

"Molecular switches" on mGluR allosteric ligands that modulate modes of pharmacology. Biochemistry (2011) 1.89

Progress toward positive allosteric modulators of the metabotropic glutamate receptor subtype 5 (mGluR5). ACS Chem Neurosci (2011) 1.44

Probing the metabotropic glutamate receptor 5 (mGlu₅) positive allosteric modulator (PAM) binding pocket: discovery of point mutations that engender a "molecular switch" in PAM pharmacology. Mol Pharmacol (2013) 1.05

Biotransformation of a novel positive allosteric modulator of metabotropic glutamate receptor subtype 5 contributes to seizure-like adverse events in rats involving a receptor agonism-dependent mechanism. Drug Metab Dispos (2013) 1.04

Synthesis and SAR of centrally active mGlu5 positive allosteric modulators based on an aryl acetylenic bicyclic lactam scaffold. Bioorg Med Chem Lett (2011) 1.04

A novel metabotropic glutamate receptor 5 positive allosteric modulator acts at a unique site and confers stimulus bias to mGlu5 signaling. Mol Pharmacol (2013) 1.04

Drugs for allosteric sites on receptors. Annu Rev Pharmacol Toxicol (2013) 1.04

Novel Allosteric Modulators of G Protein-coupled Receptors. J Biol Chem (2015) 1.02

Practical Strategies and Concepts in GPCR Allosteric Modulator Discovery: Recent Advances with Metabotropic Glutamate Receptors. Chem Rev (2016) 0.97

Optimization of an ether series of mGlu5 positive allosteric modulators: molecular determinants of MPEP-site interaction crossover. Bioorg Med Chem Lett (2012) 0.94

Tetrahydronaphthyridine and dihydronaphthyridinone ethers as positive allosteric modulators of the metabotropic glutamate receptor 5 (mGlu₅). J Med Chem (2014) 0.92

Discovery of VU0409106: A negative allosteric modulator of mGlu5 with activity in a mouse model of anxiety. Bioorg Med Chem Lett (2013) 0.88

Identification of specific ligand-receptor interactions that govern binding and cooperativity of diverse modulators to a common metabotropic glutamate receptor 5 allosteric site. ACS Chem Neurosci (2014) 0.86

Substituted 1-Phenyl-3-(pyridin-2-yl)urea negative allosteric modulators of mGlu5: discovery of a new tool compound VU0463841 with activity in rat models of cocaine addiction. ACS Chem Neurosci (2013) 0.84

Synthesis and SAR of a novel metabotropic glutamate receptor 4 (mGlu4) antagonist: unexpected 'molecular switch' from a closely related mGlu4 positive allosteric modulator. Bioorg Med Chem Lett (2011) 0.83

Molecular Insights into Metabotropic Glutamate Receptor Allosteric Modulation. Mol Pharmacol (2015) 0.83

Discovery of a Selective and CNS Penetrant Negative Allosteric Modulator of Metabotropic Glutamate Receptor Subtype 3 with Antidepressant and Anxiolytic Activity in Rodents. J Med Chem (2015) 0.82

Discovery and SAR of a novel series of non-MPEP site mGlu₅ PAMs based on an aryl glycine sulfonamide scaffold. Bioorg Med Chem Lett (2012) 0.82

Progress toward advanced understanding of metabotropic glutamate receptors: structure, signaling and therapeutic indications. Cell Signal (2014) 0.81

Discovery of VU0431316: a negative allosteric modulator of mGlu5 with activity in a mouse model of anxiety. Bioorg Med Chem Lett (2014) 0.81

Positive allosteric modulators of metabotropic glutamate 2 receptors in schizophrenia treatment. Trends Neurosci (2015) 0.80

Articles cited by this

Pharmacology and functions of metabotropic glutamate receptors. Annu Rev Pharmacol Toxicol (1997) 10.26

Allosteric modulators of GPCRs: a novel approach for the treatment of CNS disorders. Nat Rev Drug Discov (2009) 6.69

Pharmacological agents acting at subtypes of metabotropic glutamate receptors. Neuropharmacology (1999) 4.48

2-Methyl-6-(phenylethynyl)-pyridine (MPEP), a potent, selective and systemically active mGlu5 receptor antagonist. Neuropharmacology (1999) 3.25

Activation of metabotropic glutamate receptors as a novel approach for the treatment of schizophrenia. Trends Pharmacol Sci (2008) 3.22

Discovery of positive allosteric modulators for the metabotropic glutamate receptor subtype 5 from a series of N-(1,3-diphenyl-1H- pyrazol-5-yl)benzamides that potentiate receptor function in vivo. J Med Chem (2004) 2.46

Challenges in the development of mGluR5 positive allosteric modulators: the discovery of CPPHA. Bioorg Med Chem Lett (2006) 2.17

A close structural analog of 2-methyl-6-(phenylethynyl)-pyridine acts as a neutral allosteric site ligand on metabotropic glutamate receptor subtype 5 and blocks the effects of multiple allosteric modulators. Mol Pharmacol (2005) 2.03

Metabotropic glutamate receptor subtype 5 antagonists MPEP and MTEP. CNS Drug Rev (2006) 1.86

Synthesis and SAR of a mGluR5 allosteric partial antagonist lead: unexpected modulation of pharmacology with slight structural modifications to a 5-(phenylethynyl)pyrimidine scaffold. Bioorg Med Chem Lett (2008) 1.78

Discovery of molecular switches that modulate modes of metabotropic glutamate receptor subtype 5 (mGlu5) pharmacology in vitro and in vivo within a series of functionalized, regioisomeric 2- and 5-(phenylethynyl)pyrimidines. J Med Chem (2009) 1.46

Synthesis, SAR and unanticipated pharmacological profiles of analogues of the mGluR5 ago-potentiator ADX-47273. ChemMedChem (2009) 1.29

Discovery of a Novel Chemical Class of mGlu(5) Allosteric Ligands with Distinct Modes of Pharmacology. ACS Chem Neurosci (2010) 1.24

Positive and negative allosteric modulation of metabotropic glutamate receptors: emerging therapeutic potential. Pharmacol Ther (2004) 1.20

Recent progress in the discovery and development of negative allosteric modulators of mGluR5. Curr Opin Drug Discov Devel (2009) 1.16

Discovery and SAR of novel mGluR5 non-competitive antagonists not based on an MPEP chemotype. Bioorg Med Chem Lett (2009) 1.13

3-Cyano-5-fluoro-N-arylbenzamides as negative allosteric modulators of mGlu(5): Identification of easily prepared tool compounds with CNS exposure in rats. Bioorg Med Chem Lett (2010) 1.05

Synthesis and SAR of novel, non-MPEP chemotype mGluR5 NAMs identified by functional HTS. Bioorg Med Chem Lett (2009) 0.99

Hit-to-lead optimization of disubstituted oxadiazoles and tetrazoles as mGluR5 NAMs. Bioorg Med Chem Lett (2010) 0.85

Articles by these authors

Allosteric modulators of GPCRs: a novel approach for the treatment of CNS disorders. Nat Rev Drug Discov (2009) 6.69

Metabotropic glutamate receptors: physiology, pharmacology, and disease. Annu Rev Pharmacol Toxicol (2010) 4.77

The top prescription drugs of 2009 in the US: CNS therapeutics rank among highest grossing. ACS Chem Neurosci (2010) 4.20

The Akt/PKB pathway: molecular target for cancer drug discovery. Oncogene (2005) 3.42

Activation of metabotropic glutamate receptors as a novel approach for the treatment of schizophrenia. Trends Pharmacol Sci (2008) 3.22

A novel selective positive allosteric modulator of metabotropic glutamate receptor subtype 5 has in vivo activity and antipsychotic-like effects in rat behavioral models. J Pharmacol Exp Ther (2004) 2.83

Design of isoform-selective phospholipase D inhibitors that modulate cancer cell invasiveness. Nat Chem Biol (2009) 2.72

Application of combinatorial chemistry science on modern drug discovery. J Comb Chem (2008) 2.64

Discovery of positive allosteric modulators for the metabotropic glutamate receptor subtype 5 from a series of N-(1,3-diphenyl-1H- pyrazol-5-yl)benzamides that potentiate receptor function in vivo. J Med Chem (2004) 2.46

Subtype-selective allosteric modulators of muscarinic receptors for the treatment of CNS disorders. Trends Pharmacol Sci (2009) 2.38

Novel selective allosteric activator of the M1 muscarinic acetylcholine receptor regulates amyloid processing and produces antipsychotic-like activity in rats. J Neurosci (2008) 2.34

Centrally active allosteric potentiators of the M4 muscarinic acetylcholine receptor reverse amphetamine-induced hyperlocomotor activity in rats. J Pharmacol Exp Ther (2008) 2.29

In vivo structure-activity relationship study of dorsomorphin analogues identifies selective VEGF and BMP inhibitors. ACS Chem Biol (2010) 2.29

A family of highly selective allosteric modulators of the metabotropic glutamate receptor subtype 5. Mol Pharmacol (2003) 2.27

Tumor cell sensitization to apoptotic stimuli by selective inhibition of specific Akt/PKB family members. Mol Cancer Ther (2005) 2.23

A novel selective allosteric modulator potentiates the activity of native metabotropic glutamate receptor subtype 5 in rat forebrain. J Pharmacol Exp Ther (2004) 2.17

Challenges in the development of mGluR5 positive allosteric modulators: the discovery of CPPHA. Bioorg Med Chem Lett (2006) 2.17

The top prescription drugs of 2010 in the United States: antipsychotics show strong growth. ACS Chem Neurosci (2011) 2.16

A novel assay of Gi/o-linked G protein-coupled receptor coupling to potassium channels provides new insights into the pharmacology of the group III metabotropic glutamate receptors. Mol Pharmacol (2008) 2.12

Allosteric modulation of seven transmembrane spanning receptors: theory, practice, and opportunities for central nervous system drug discovery. J Med Chem (2012) 2.10

A close structural analog of 2-methyl-6-(phenylethynyl)-pyridine acts as a neutral allosteric site ligand on metabotropic glutamate receptor subtype 5 and blocks the effects of multiple allosteric modulators. Mol Pharmacol (2005) 2.03

Allosteric modulation of group III metabotropic glutamate receptor 4: a potential approach to Parkinson's disease treatment. Proc Natl Acad Sci U S A (2003) 1.98

N-desmethylclozapine, an allosteric agonist at muscarinic 1 receptor, potentiates N-methyl-D-aspartate receptor activity. Proc Natl Acad Sci U S A (2003) 1.96

Discovery, characterization, and antiparkinsonian effect of novel positive allosteric modulators of metabotropic glutamate receptor 4. Mol Pharmacol (2008) 1.94

Discovery of novel allosteric modulators of metabotropic glutamate receptor subtype 5 reveals chemical and functional diversity and in vivo activity in rat behavioral models of anxiolytic and antipsychotic activity. Mol Pharmacol (2010) 1.93

"Molecular switches" on mGluR allosteric ligands that modulate modes of pharmacology. Biochemistry (2011) 1.89

Selective activation of the M1 muscarinic acetylcholine receptor achieved by allosteric potentiation. Proc Natl Acad Sci U S A (2009) 1.87

Loss of Phosphatase and Tensin homologue deleted on chromosome 10 engages ErbB3 and insulin-like growth factor-I receptor signaling to promote antiestrogen resistance in breast cancer. Cancer Res (2009) 1.84

An allosteric potentiator of M4 mAChR modulates hippocampal synaptic transmission. Nat Chem Biol (2007) 1.83

Structure of a class C GPCR metabotropic glutamate receptor 1 bound to an allosteric modulator. Science (2014) 1.81

mGluR5 positive allosteric modulators facilitate both hippocampal LTP and LTD and enhance spatial learning. Neuropsychopharmacology (2009) 1.80

Glutamate-based therapeutic approaches: allosteric modulators of metabotropic glutamate receptors. Curr Opin Pharmacol (2005) 1.80

Synthesis and SAR of a mGluR5 allosteric partial antagonist lead: unexpected modulation of pharmacology with slight structural modifications to a 5-(phenylethynyl)pyrimidine scaffold. Bioorg Med Chem Lett (2008) 1.78

A novel selective muscarinic acetylcholine receptor subtype 1 antagonist reduces seizures without impairing hippocampus-dependent learning. Mol Pharmacol (2009) 1.76

Inhibition of the TRPC5 ion channel protects the kidney filter. J Clin Invest (2013) 1.76

G-protein-coupled receptors: from classical modes of modulation to allosteric mechanisms. ACS Chem Biol (2008) 1.76

Substituent effects of N-(1,3-diphenyl-1H-pyrazol-5-yl)benzamides on positive allosteric modulation of the metabotropic glutamate-5 receptor in rat cortical astrocytes. J Med Chem (2006) 1.73

The top prescription drugs of 2011 in the United States: antipsychotics and antidepressants once again lead CNS therapeutics. ACS Chem Neurosci (2012) 1.72

Discovery and characterization of novel allosteric potentiators of M1 muscarinic receptors reveals multiple modes of activity. Mol Pharmacol (2008) 1.68

Phospholipase D: enzymology, functionality, and chemical modulation. Chem Rev (2011) 1.66

Biphenyl-indanone A, a positive allosteric modulator of the metabotropic glutamate receptor subtype 2, has antipsychotic- and anxiolytic-like effects in mice. J Pharmacol Exp Ther (2006) 1.60

Synthesis and evaluation of a series of heterobiarylamides that are centrally penetrant metabotropic glutamate receptor 4 (mGluR4) positive allosteric modulators (PAMs). J Med Chem (2009) 1.59

Discovery of the first highly M5-preferring muscarinic acetylcholine receptor ligand, an M5 positive allosteric modulator derived from a series of 5-trifluoromethoxy N-benzyl isatins. J Med Chem (2009) 1.57

A selective allosteric potentiator of the M1 muscarinic acetylcholine receptor increases activity of medial prefrontal cortical neurons and restores impairments in reversal learning. J Neurosci (2009) 1.57

N-{4-Chloro-2-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]phenyl}-2-hydroxybenzamide (CPPHA) acts through a novel site as a positive allosteric modulator of group 1 metabotropic glutamate receptors. Mol Pharmacol (2007) 1.56

Group III metabotropic glutamate receptor-mediated modulation of the striatopallidal synapse. J Neurosci (2003) 1.55

Inhibition of mammalian target of rapamycin is required for optimal antitumor effect of HER2 inhibitors against HER2-overexpressing cancer cells. Clin Cancer Res (2009) 1.53

Discovery and characterization of novel subtype-selective allosteric agonists for the investigation of M(1) receptor function in the central nervous system. ACS Chem Neurosci (2010) 1.52

Direct and indirect modulation of the N-methyl D-aspartate receptor. Curr Drug Targets CNS Neurol Disord (2002) 1.49

Efficient synthesis of imidazoles from aldehydes and 1,2-diketones using microwave irradiation. Org Lett (2004) 1.48

mGluR4-positive allosteric modulation as potential treatment for Parkinson's disease. Future Med Chem (2009) 1.47

Interaction of novel positive allosteric modulators of metabotropic glutamate receptor 5 with the negative allosteric antagonist site is required for potentiation of receptor responses. Mol Pharmacol (2007) 1.46

Functional impact of allosteric agonist activity of selective positive allosteric modulators of metabotropic glutamate receptor subtype 5 in regulating central nervous system function. Mol Pharmacol (2011) 1.46

Discovery of molecular switches that modulate modes of metabotropic glutamate receptor subtype 5 (mGlu5) pharmacology in vitro and in vivo within a series of functionalized, regioisomeric 2- and 5-(phenylethynyl)pyrimidines. J Med Chem (2009) 1.46

Small-molecule screen identifies inhibitors of the neuronal K-Cl cotransporter KCC2. Proc Natl Acad Sci U S A (2009) 1.45

Development of a selective small-molecule inhibitor of Kir1.1, the renal outer medullary potassium channel. Mol Pharmacol (2010) 1.45

Glutamate receptors and Parkinson's disease: opportunities for intervention. Drugs Aging (2003) 1.44

Alzheimer's disease: development of disease-modifying treatments is the challenge for our generation. ACS Chem Neurosci (2012) 1.43

A selective allosteric potentiator of metabotropic glutamate (mGlu) 2 receptors has effects similar to an orthosteric mGlu2/3 receptor agonist in mouse models predictive of antipsychotic activity. J Pharmacol Exp Ther (2005) 1.43

A selective positive allosteric modulator of metabotropic glutamate receptor subtype 2 blocks a hallucinogenic drug model of psychosis. Mol Pharmacol (2007) 1.42

Allosteric potentiators of metabotropic glutamate receptor subtype 5 have differential effects on different signaling pathways in cortical astrocytes. J Pharmacol Exp Ther (2005) 1.42