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Biased M receptor-positive allosteric modulators reveal role of phospholipase D in M-dependent rodent cortical plasticity.
Moran SP, Xiang Z, Doyle CA, Maksymetz J, Lv X, Faltin S, Fisher NM, Niswender CM, Rook JM, Lindsley CW, Conn PJ
(2019) Sci Signal 12:
MeSH Terms: Allosteric Site, Animals, CHO Cells, Calcium, Cerebral Cortex, Cognition, Cricetinae, Cricetulus, Electrophysiology, Female, Humans, Long-Term Synaptic Depression, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Neuronal Plasticity, Phospholipase D, Prefrontal Cortex, Receptor, Muscarinic M1, Signal Transduction, Type C Phospholipases
Show Abstract · Added March 3, 2020
Highly selective, positive allosteric modulators (PAMs) of the M subtype of muscarinic acetylcholine receptor have emerged as an exciting new approach to potentially improve cognitive function in patients suffering from Alzheimer's disease and schizophrenia. Discovery programs have produced a structurally diverse range of M receptor PAMs with distinct pharmacological properties, including different extents of agonist activity and differences in signal bias. This includes biased M receptor PAMs that can potentiate coupling of the receptor to activation of phospholipase C (PLC) but not phospholipase D (PLD). However, little is known about the role of PLD in M receptor signaling in native systems, and it is not clear whether biased M PAMs display differences in modulating M-mediated responses in native tissue. Using PLD inhibitors and PLD knockout mice, we showed that PLD was necessary for the induction of M-dependent long-term depression (LTD) in the prefrontal cortex (PFC). Furthermore, biased M PAMs that did not couple to PLD not only failed to potentiate orthosteric agonist-induced LTD but also blocked M-dependent LTD in the PFC. In contrast, biased and nonbiased M PAMs acted similarly in potentiating M-dependent electrophysiological responses that were PLD independent. These findings demonstrate that PLD plays a critical role in the ability of M PAMs to modulate certain central nervous system (CNS) functions and that biased M PAMs function differently in brain regions implicated in cognition.
Copyright © 2019 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.
0 Communities
2 Members
0 Resources
22 MeSH Terms
Differential Pharmacology and Binding of mGlu Receptor Allosteric Modulators.
O'Brien DE, Shaw DM, Cho HP, Cross AJ, Wesolowski SS, Felts AS, Bergare J, Elmore CS, Lindsley CW, Niswender CM, Conn PJ
(2018) Mol Pharmacol 93: 526-540
MeSH Terms: Allosteric Regulation, Allosteric Site, Animals, Cell Line, Glutamic Acid, HEK293 Cells, Humans, Ligands, Mutagenesis, Protein Binding, Radioligand Assay, Rats, Receptors, Metabotropic Glutamate
Show Abstract · Added March 3, 2020
Allosteric modulation of metabotropic glutamate receptor 2 (mGlu) has demonstrated efficacy in preclinical rodent models of several brain disorders, leading to industry and academic drug discovery efforts. Although the pharmacology and binding sites of some mGlu allosteric modulators have been characterized previously, questions remain about the nature of the allosteric mechanism of cooperativity with glutamate and whether structurally diverse allosteric modulators bind in an identical manner to specific allosteric sites. To further investigate the in vitro pharmacology of mGlu allosteric modulators, we developed and characterized a novel mGlu positive allosteric modulator (PAM) radioligand in parallel with functional studies of a structurally diverse set of mGlu PAMs and negative allosteric modulators (NAMs). Using an operational model of allosterism to analyze the functional data, we found that PAMs affect both the affinity and efficacy of glutamate at mGlu, whereas NAMs predominantly affect the efficacy of glutamate in our assay system. More importantly, we found that binding of a novel mGlu PAM radioligand was inhibited by multiple structurally diverse PAMs and NAMs, indicating that they may bind to the mGlu allosteric site labeled with the novel mGlu PAM radioligand; however, further studies suggested that these allosteric modulators do not all interact with the radioligand in an identical manner. Together, these findings provide new insights into the binding sites and modes of efficacy of different structurally and functionally distinct mGlu allosteric modulators and suggest that different ligands either interact with distinct sites or adapt different binding poses to shared allosteric site(s).
Copyright © 2018 by The American Society for Pharmacology and Experimental Therapeutics.
0 Communities
1 Members
0 Resources
MeSH Terms
Competition and allostery govern substrate selectivity of cyclooxygenase-2.
Mitchener MM, Hermanson DJ, Shockley EM, Brown HA, Lindsley CW, Reese J, Rouzer CA, Lopez CF, Marnett LJ
(2015) Proc Natl Acad Sci U S A 112: 12366-71
MeSH Terms: Algorithms, Allosteric Regulation, Allosteric Site, Animals, Arachidonic Acid, Arachidonic Acids, Binding, Competitive, Catalytic Domain, Cell Line, Computer Simulation, Cyclooxygenase 2, Endocannabinoids, Glycerides, Kinetics, Macrophages, Mice, Oxidation-Reduction, Prostaglandins, Protein Binding, Protein Multimerization, Sf9 Cells, Spodoptera, Substrate Specificity, Zymosan
Show Abstract · Added February 15, 2016
Cyclooxygenase-2 (COX-2) oxygenates arachidonic acid (AA) and its ester analog, 2-arachidonoylglycerol (2-AG), to prostaglandins (PGs) and prostaglandin glyceryl esters (PG-Gs), respectively. Although the efficiency of oxygenation of these substrates by COX-2 in vitro is similar, cellular biosynthesis of PGs far exceeds that of PG-Gs. Evidence that the COX enzymes are functional heterodimers suggests that competitive interaction of AA and 2-AG at the allosteric site of COX-2 might result in differential regulation of the oxygenation of the two substrates when both are present. Modulation of AA levels in RAW264.7 macrophages uncovered an inverse correlation between cellular AA levels and PG-G biosynthesis. In vitro kinetic analysis using purified protein demonstrated that the inhibition of 2-AG oxygenation by high concentrations of AA far exceeded the inhibition of AA oxygenation by high concentrations of 2-AG. An unbiased systems-based mechanistic model of the kinetic data revealed that binding of AA or 2-AG at the allosteric site of COX-2 results in a decreased catalytic efficiency of the enzyme toward 2-AG, whereas 2-AG binding at the allosteric site increases COX-2's efficiency toward AA. The results suggest that substrates interact with COX-2 via multiple potential complexes involving binding to both the catalytic and allosteric sites. Competition between AA and 2-AG for these sites, combined with differential allosteric modulation, gives rise to a complex interplay between the substrates, leading to preferential oxygenation of AA.
1 Communities
4 Members
0 Resources
24 MeSH Terms
Molecular Insights into Metabotropic Glutamate Receptor Allosteric Modulation.
Gregory KJ, Conn PJ
(2015) Mol Pharmacol 88: 188-202
MeSH Terms: Allosteric Site, Benzhydryl Compounds, Central Nervous System, Drug Design, Humans, Molecular Targeted Therapy, Protein Conformation, Receptors, Metabotropic Glutamate
Show Abstract · Added February 18, 2016
The metabotropic glutamate (mGlu) receptors are a group of eight family C G protein-coupled receptors that are expressed throughout the central nervous system (CNS) and periphery. Within the CNS the different subtypes are found in neurons, both pre- and/or postsynaptically, where they mediate modulatory roles and in glial cells. The mGlu receptor family provides attractive targets for numerous psychiatric and neurologic disorders, with the majority of discovery programs focused on targeting allosteric sites, with allosteric ligands now available for all mGlu receptor subtypes. However, the development of allosteric ligands remains challenging. Biased modulation, probe dependence, and molecular switches all contribute to the complex molecular pharmacology exhibited by mGlu receptor allosteric ligands. In recent years we have made significant progress in our understanding of this molecular complexity coupled with an increased understanding of the structural basis of mGlu allosteric modulation.
Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics.
0 Communities
1 Members
0 Resources
8 MeSH Terms
Discovery and SAR of muscarinic receptor subtype 1 (M1) allosteric activators from a molecular libraries high throughput screen. Part 1: 2,5-dibenzyl-2H-pyrazolo[4,3-c]quinolin-3(5H)-ones as positive allosteric modulators.
Han C, Chatterjee A, Noetzel MJ, Panarese JD, Smith E, Chase P, Hodder P, Niswender C, Conn PJ, Lindsley CW, Stauffer SR
(2015) Bioorg Med Chem Lett 25: 384-8
MeSH Terms: Allosteric Regulation, Allosteric Site, Drug Discovery, Humans, Models, Molecular, Molecular Docking Simulation, Molecular Structure, Pyrazoles, Quinolines, Quinolones, Receptor, Muscarinic M1, Small Molecule Libraries, Structure-Activity Relationship
Show Abstract · Added February 18, 2016
Results from a 2012 high-throughput screen of the NIH Molecular Libraries Small Molecule Repository (MLSMR) against the human muscarinic receptor subtype 1 (M1) for positive allosteric modulators is reported. A content-rich screen utilizing an intracellular calcium mobilization triple-addition protocol allowed for assessment of all three modes of pharmacology at M1, including agonist, positive allosteric modulator, and antagonist activities in a single screening platform. We disclose a dibenzyl-2H-pyrazolo[4,3-c]quinolin-3(5H)-one hit (DBPQ, CID 915409) and examine N-benzyl pharmacophore/SAR relationships versus previously reported quinolin-3(5H)-ones and isatins, including ML137. SAR and consideration of recently reported crystal structures, homology modeling, and structure-function relationships using point mutations suggests a shared binding mode orientation at the putative common allosteric binding site directed by the pendant N-benzyl substructure.
Copyright © 2014 Elsevier Ltd. All rights reserved.
0 Communities
2 Members
0 Resources
13 MeSH Terms
Mutational analysis of cysteine residues of the insect odorant co-receptor (Orco) from Drosophila melanogaster reveals differential effects on agonist- and odorant-tuning receptor-dependent activation.
Turner RM, Derryberry SL, Kumar BN, Brittain T, Zwiebel LJ, Newcomb RD, Christie DL
(2014) J Biol Chem 289: 31837-45
MeSH Terms: Allosteric Site, Animals, Biotinylation, Calcium, Cysteine, DNA Mutational Analysis, Drosophila Proteins, Drosophila melanogaster, Epitopes, HEK293 Cells, Humans, Ion Channels, Kinetics, Mutagenesis, Site-Directed, Mutation, Odorants, Patch-Clamp Techniques, Protein Binding, Protein Structure, Tertiary, Receptors, Odorant, Thioglycolates, Triazoles
Show Abstract · Added February 19, 2015
Insect odorant receptors are heteromeric odorant-gated cation channels comprising a conventional odorant-sensitive tuning receptor (ORx) and a highly conserved co-receptor known as Orco. Orco is found only in insects, and very little is known about its structure and the mechanism leading to channel activation. In the absence of an ORx, Orco forms homomeric channels that can be activated by a synthetic agonist, VUAA1. Drosophila melanogaster Orco (DmelOrco) contains eight cysteine amino acid residues, six of which are highly conserved. In this study, we replaced individual cysteine residues with serine or alanine and expressed Orco mutants in Flp-In 293 T-Rex cells. Changes in intracellular Ca(2+) levels were used to determine responses to VUAA1. Replacement of two cysteines (Cys-429 and Cys-449) in a predicted intracellular loop (ICL3), individually or together, gave variants that all showed similar increases in the rate of response and sensitivity to VUAA1 compared with wild-type DmelOrco. Kinetic modeling indicated that the response of the Orco mutants to VUAA1 was faster than wild-type Orco. The enhanced sensitivity and faster response of the Cys mutants was confirmed by whole-cell voltage clamp electrophysiology. In contrast to the results from direct agonist activation of Orco, the two cysteine replacement mutants when co-expressed with a tuning receptor (DmelOR22a) showed an ∼10-fold decrease in potency for activation by 2-methyl hexanoate. Our work has shown that intracellular loop 3 is important for Orco channel activation. Importantly, this study also suggests differences in the structural requirements for the activation of homomeric and heteromeric Orco channel complexes.
© 2014 by The American Society for Biochemistry and Molecular Biology, Inc.
0 Communities
1 Members
0 Resources
22 MeSH Terms
Discovery of VU0431316: a negative allosteric modulator of mGlu5 with activity in a mouse model of anxiety.
Bates BS, Rodriguez AL, Felts AS, Morrison RD, Venable DF, Blobaum AL, Byers FW, Lawson KP, Daniels JS, Niswender CM, Jones CK, Conn PJ, Lindsley CW, Emmitte KA
(2014) Bioorg Med Chem Lett 24: 3307-14
MeSH Terms: Allosteric Site, Animals, Anxiety, Disease Models, Animal, Dose-Response Relationship, Drug, Drug Discovery, Humans, Male, Mice, Molecular Structure, Picolinic Acids, Pyrazines, Rats, Rats, Sprague-Dawley, Receptor, Metabotropic Glutamate 5, Structure-Activity Relationship
Show Abstract · Added February 19, 2015
Development of SAR in an aryl ether series of mGlu5 NAMs leading to the identification of pyrazine analog VU0431316 is described in this Letter. VU0431316 is a potent and selective non-competitive antagonist of mGlu5 that binds at a known allosteric binding site. VU0431316 demonstrates an attractive DMPK profile, including moderate clearance and good bioavailability in rats. Intraperitoneal (IP) dosing of VU0431316 in a mouse marble burying model of anxiety, an assay known to be sensitive to mGlu5 antagonists and other anxiolytics, produced dose proportional effects.
Copyright © 2014 Elsevier Ltd. All rights reserved.
0 Communities
3 Members
0 Resources
16 MeSH Terms
Structure of a class C GPCR metabotropic glutamate receptor 1 bound to an allosteric modulator.
Wu H, Wang C, Gregory KJ, Han GW, Cho HP, Xia Y, Niswender CM, Katritch V, Meiler J, Cherezov V, Conn PJ, Stevens RC
(2014) Science 344: 58-64
MeSH Terms: Allosteric Regulation, Allosteric Site, Amino Acid Sequence, Benzamides, Binding Sites, Cholesterol, Crystallography, X-Ray, Humans, Hydrophobic and Hydrophilic Interactions, Ligands, Models, Molecular, Molecular Sequence Data, Mutation, Protein Conformation, Protein Multimerization, Protein Structure, Secondary, Protein Structure, Tertiary, Receptors, Metabotropic Glutamate, Structure-Activity Relationship, Thiazoles
Show Abstract · Added January 24, 2015
The excitatory neurotransmitter glutamate induces modulatory actions via the metabotropic glutamate receptors (mGlus), which are class C G protein-coupled receptors (GPCRs). We determined the structure of the human mGlu1 receptor seven-transmembrane (7TM) domain bound to a negative allosteric modulator, FITM, at a resolution of 2.8 angstroms. The modulator binding site partially overlaps with the orthosteric binding sites of class A GPCRs but is more restricted than most other GPCRs. We observed a parallel 7TM dimer mediated by cholesterols, which suggests that signaling initiated by glutamate's interaction with the extracellular domain might be mediated via 7TM interactions within the full-length receptor dimer. A combination of crystallography, structure-activity relationships, mutagenesis, and full-length dimer modeling provides insights about the allosteric modulation and activation mechanism of class C GPCRs.
1 Communities
3 Members
0 Resources
20 MeSH Terms
A Duplexed High-Throughput Screen to Identify Allosteric Modulators of the Glucagon-Like Peptide 1 and Glucagon Receptors.
Morris LC, Days EL, Turney M, Mi D, Lindsley CW, Weaver CD, Niswender KD
(2014) J Biomol Screen 19: 847-58
MeSH Terms: Allosteric Regulation, Allosteric Site, Animals, Binding Sites, CHO Cells, Calcium, Cell Line, Cell Line, Tumor, Cricetinae, Cricetulus, Cyclic AMP, Disease Progression, Exenatide, Glucagon-Like Peptide 1, Glucose, High-Throughput Screening Assays, Humans, Liraglutide, Peptides, Receptors, Glucagon, Recombinant Proteins, Signal Transduction, Venoms
Show Abstract · Added August 14, 2014
Injectable, degradation-resistant peptide agonists for the glucagon-like peptide 1 (GLP-1) receptor (GLP-1R), such as exenatide and liraglutide, activate the GLP-1R via a complex orthosteric-binding site and are effective therapeutics for glycemic control in type 2 diabetes. Orally bioavailable orthosteric small-molecule agonists are unlikely to be developed, whereas positive allosteric modulators (PAMs) may offer an improved therapeutic profile. We hypothesize that allosteric modulators of the GLP-1R would increase the potency and efficacy of native GLP-1 in a spatial and temporally preserved manner and/or may improve efficacy or side effects of injectable analogs. We report the design, optimization, and initial results of a duplexed high-throughput screen in which cell lines overexpressing either the GLP-1R or the glucagon receptor were coplated, loaded with a calcium-sensitive dye, and probed in a three-phase assay to identify agonists, antagonists, and potentiators of GLP-1, and potentiators of glucagon. 175,000 compounds were initially screened, and progression through secondary assays yielded 98 compounds with a variety of activities at the GLP-1R. Here, we describe five compounds possessing different patterns of modulation of the GLP-1R. These data uncover PAMs that may offer a drug-development pathway to enhancing in vivo efficacy of both endogenous GLP-1 and peptide analogs.
© 2014 Society for Laboratory Automation and Screening.
0 Communities
3 Members
0 Resources
23 MeSH Terms
Discovery of VU0409106: A negative allosteric modulator of mGlu5 with activity in a mouse model of anxiety.
Felts AS, Rodriguez AL, Morrison RD, Venable DF, Manka JT, Bates BS, Blobaum AL, Byers FW, Daniels JS, Niswender CM, Jones CK, Conn PJ, Lindsley CW, Emmitte KA
(2013) Bioorg Med Chem Lett 23: 5779-85
MeSH Terms: Allosteric Regulation, Allosteric Site, Animals, Anxiety, Benzamides, Mice, Receptor, Metabotropic Glutamate 5, Structure-Activity Relationship, Thiazoles
Show Abstract · Added February 19, 2015
Development of SAR in an aryl ether series of mGlu5 NAMs leading to the identification of tool compound VU0409106 is described in this Letter. VU0409106 is a potent and selective negative allosteric modulator of mGlu5 that binds at the known allosteric binding site and demonstrates good CNS exposure following intraperitoneal dosing in mice. VU0409106 also proved efficacious in a mouse marble burying model of anxiety, an assay known to be sensitive to mGlu5 antagonists as well as clinically efficacious anxiolytics.
Copyright © 2013 Elsevier Ltd. All rights reserved.
0 Communities
3 Members
0 Resources
9 MeSH Terms