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Toxicity and repair of DNA adducts produced by the natural product yatakemycin.
Mullins EA, Shi R, Eichman BF
(2017) Nat Chem Biol 13: 1002-1008
MeSH Terms: Biological Products, DNA Adducts, DNA Damage, DNA Repair, Drug Resistance, Bacterial, Indoles, Molecular Structure, Pyrroles
Show Abstract · Added August 26, 2019
Yatakemycin (YTM) is an extraordinarily toxic DNA alkylating agent with potent antimicrobial and antitumor properties and is the most recent addition to the CC-1065 and duocarmycin family of natural products. Though bulky DNA lesions the size of those produced by YTM are normally removed from the genome by the nucleotide-excision repair (NER) pathway, YTM adducts are also a substrate for the bacterial DNA glycosylases AlkD and YtkR2, unexpectedly implicating base-excision repair (BER) in their elimination. The reason for the extreme toxicity of these lesions and the molecular basis for the way they are eliminated by BER have been unclear. Here, we describe the structural and biochemical properties of YTM adducts that are responsible for their toxicity, and define the mechanism by which they are excised by AlkD. These findings delineate an alternative strategy for repair of bulky DNA damage and establish the cellular utility of this pathway relative to that of NER.
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Discovery and characterization of a novel series of N-phenylsulfonyl-1H-pyrrole picolinamides as positive allosteric modulators of the metabotropic glutamate receptor 4 (mGlu4).
Gogliotti RD, Blobaum AL, Morrison RM, Daniels JS, Salovich JM, Cheung YY, Rodriguez AL, Loch MT, Conn PJ, Lindsley CW, Niswender CM, Hopkins CR
(2016) Bioorg Med Chem Lett 26: 2984-2987
MeSH Terms: Allosteric Regulation, Animals, Microsomes, Liver, Picolinic Acids, Pyrroles, Rats, Receptors, Metabotropic Glutamate, Structure-Activity Relationship, Sulfonamides, Triazoles
Show Abstract · Added April 6, 2017
Herein we report the synthesis and characterization of a novel series of N-phenylsulfonyl-1H-pyrrole picolinamides as novel positive allosteric modulators of mGlu4. We detail our work towards finding phenyl replacements for the core scaffold of previously reported phenyl sulfonamides and phenyl sulfone compounds. Our efforts culminated in the identification of N-(1-((3,4-dimethylphenyl)sulfonyl)-1H-pyrrol-3-yl)picolinamide as a potent PAM of mGlu4.
Copyright © 2016 Elsevier Ltd. All rights reserved.
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10 MeSH Terms
Further optimization of the M1 PAM VU0453595: Discovery of novel heterobicyclic core motifs with improved CNS penetration.
Panarese JD, Cho HP, Adams JJ, Nance KD, Garcia-Barrantes PM, Chang S, Morrison RD, Blobaum AL, Niswender CM, Stauffer SR, Conn PJ, Lindsley CW
(2016) Bioorg Med Chem Lett 26: 3822-5
MeSH Terms: Allosteric Regulation, Animals, Central Nervous System, Central Nervous System Agents, Dose-Response Relationship, Drug, Drug Discovery, Heterocyclic Compounds, Molecular Structure, Pyridines, Pyrroles, Rats, Receptor, Muscarinic M1, Structure-Activity Relationship
Show Abstract · Added April 6, 2017
This Letter describes the continued chemical optimization of the VU0453595 series of M1 positive allosteric modulators (PAMs). By surveying alternative 5,6- and 6,6-heterobicylic cores for the 6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-5-one core of VU453595, we found new cores that engendered not only comparable or improved M1 PAM potency, but significantly improved CNS distribution (Kps 0.3-3.1). Moreover, this campaign provided fundamentally distinct M1 PAM chemotypes, greatly expanding the available structural diversity for this valuable CNS target, devoid of hydrogen-bond donors.
Copyright © 2016 Elsevier Ltd. All rights reserved.
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13 MeSH Terms
The DNA glycosylase AlkD uses a non-base-flipping mechanism to excise bulky lesions.
Mullins EA, Shi R, Parsons ZD, Yuen PK, David SS, Igarashi Y, Eichman BF
(2015) Nature 527: 254-8
MeSH Terms: Bacillus cereus, Base Pairing, Biocatalysis, Catalytic Domain, Crystallography, X-Ray, DNA Adducts, DNA Damage, DNA Glycosylases, DNA Repair, Indoles, Models, Molecular, Pyrroles
Show Abstract · Added November 10, 2015
Threats to genomic integrity arising from DNA damage are mitigated by DNA glycosylases, which initiate the base excision repair pathway by locating and excising aberrant nucleobases. How these enzymes find small modifications within the genome is a current area of intensive research. A hallmark of these and other DNA repair enzymes is their use of base flipping to sequester modified nucleotides from the DNA helix and into an active site pocket. Consequently, base flipping is generally regarded as an essential aspect of lesion recognition and a necessary precursor to base excision. Here we present the first, to our knowledge, DNA glycosylase mechanism that does not require base flipping for either binding or catalysis. Using the DNA glycosylase AlkD from Bacillus cereus, we crystallographically monitored excision of an alkylpurine substrate as a function of time, and reconstructed the steps along the reaction coordinate through structures representing substrate, intermediate and product complexes. Instead of directly interacting with the damaged nucleobase, AlkD recognizes aberrant base pairs through interactions with the phosphoribose backbone, while the lesion remains stacked in the DNA duplex. Quantum mechanical calculations revealed that these contacts include catalytic charge-dipole and CH-π interactions that preferentially stabilize the transition state. We show in vitro and in vivo how this unique means of recognition and catalysis enables AlkD to repair large adducts formed by yatakemycin, a member of the duocarmycin family of antimicrobial natural products exploited in bacterial warfare and chemotherapeutic trials. Bulky adducts of this or any type are not excised by DNA glycosylases that use a traditional base-flipping mechanism. Hence, these findings represent a new model for DNA repair and provide insights into catalysis of base excision.
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12 MeSH Terms
Differential CaMKII regulation by voltage-gated calcium channels in the striatum.
Pasek JG, Wang X, Colbran RJ
(2015) Mol Cell Neurosci 68: 234-43
MeSH Terms: 3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester, Animals, Calcium, Calcium Channel Agonists, Calcium Channel Blockers, Calcium Channels, L-Type, Calcium-Calmodulin-Dependent Protein Kinase Type 2, Chelating Agents, Corpus Striatum, Egtazic Acid, Enzyme Inhibitors, Gene Expression Regulation, In Vitro Techniques, Male, Mice, Mice, Inbred C57BL, Pyrroles, Receptors, Glutamate, Signal Transduction, Spider Venoms
Show Abstract · Added February 15, 2016
Calcium signaling regulates synaptic plasticity and many other functions in striatal medium spiny neurons to modulate basal ganglia function. Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) is a major calcium-dependent signaling protein that couples calcium entry to diverse cellular changes. CaMKII activation results in autophosphorylation at Thr286 and sustained calcium-independent CaMKII activity after calcium signals dissipate. However, little is known about the mechanisms regulating striatal CaMKII. To address this, mouse brain slices were treated with pharmacological modulators of calcium channels and punches of dorsal striatum were immunoblotted for CaMKII Thr286 autophosphorylation as an index of CaMKII activation. KCl depolarization increased levels of CaMKII autophosphorylation ~2-fold; this increase was blocked by an LTCC antagonist and was mimicked by treatment with pharmacological LTCC activators. The chelation of extracellular calcium robustly decreased basal CaMKII autophosphorylation within 5min and increased levels of total CaMKII in cytosolic fractions, in addition to decreasing the phosphorylation of CaMKII sites in the GluN2B subunit of NMDA receptors and the GluA1 subunit of AMPA receptors. We also found that the maintenance of basal levels of CaMKII autophosphorylation requires low-voltage gated T-type calcium channels, but not LTCCs or R-type calcium channels. Our findings indicate that CaMKII activity is dynamically regulated by multiple calcium channels in the striatum thus coupling calcium entry to key downstream substrates.
Copyright © 2015 Elsevier Inc. All rights reserved.
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Potentiation of M1 Muscarinic Receptor Reverses Plasticity Deficits and Negative and Cognitive Symptoms in a Schizophrenia Mouse Model.
Ghoshal A, Rook JM, Dickerson JW, Roop GN, Morrison RD, Jalan-Sakrikar N, Lamsal A, Noetzel MJ, Poslusney MS, Wood MR, Melancon BJ, Stauffer SR, Xiang Z, Daniels JS, Niswender CM, Jones CK, Lindsley CW, Conn PJ
(2016) Neuropsychopharmacology 41: 598-610
MeSH Terms: Animals, Antipsychotic Agents, Cognition, Disease Models, Animal, Long-Term Synaptic Depression, Male, Mice, Inbred C57BL, Mice, Knockout, Patch-Clamp Techniques, Phencyclidine, Pyridines, Pyrroles, Receptor, Muscarinic M1, Schizophrenia, Schizophrenic Psychology, Social Behavior
Show Abstract · Added February 18, 2016
Schizophrenia patients exhibit deficits in signaling of the M1 subtype of muscarinic acetylcholine receptor (mAChR) in the prefrontal cortex (PFC) and also display impaired cortical long-term depression (LTD). We report that selective activation of the M1 mAChR subtype induces LTD in PFC and that this response is completely lost after repeated administration of phencyclidine (PCP), a mouse model of schizophrenia. Furthermore, discovery of a novel, systemically active M1 positive allosteric modulator (PAM), VU0453595, allowed us to evaluate the impact of selective potentiation of M1 on induction of LTD and behavioral deficits in PCP-treated mice. Interestingly, VU0453595 fully restored impaired LTD as well as deficits in cognitive function and social interaction in these mice. These results provide critical new insights into synaptic changes that may contribute to behavioral deficits in this mouse model and support a role for selective M1 PAMs as a novel approach for the treatment of schizophrenia.
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16 MeSH Terms
Zeta inhibitory peptide (ZIP) erases long-term memories in a cockroach.
Deng Z, Lubinski AJ, Page TL
(2015) Neurobiol Learn Mem 118: 89-95
MeSH Terms: Animals, Benzophenanthridines, Carbazoles, Cockroaches, Conditioning (Psychology), Lipopeptides, Memory, Long-Term, Protein Kinase Inhibitors, Protein Synthesis Inhibitors, Pyrroles
Show Abstract · Added January 20, 2015
Recent efforts to identify the molecules that are involved in the maintenance of long-term memories in mammals have focused attention on atypical isoforms of protein kinase C (PKC). Inhibition of these kinases by either the general PKC inhibitor, chelerythrine, or the more specific inhibitor, zeta inhibitory peptide (ZIP), can abolish both long-term potentiation in the hippocampus and as well as spatial, fear, appetitive, and sensorimotor memories. These inhibitors can also abolish long-term facilitation and long-term sensitization in the mollusk Aplysia californica. We have extended these results to an insect, the cockroach Leucophaea maderae. We show that systemic injections of either chelerythrine or ZIP erase long-term olfactory memories in the cockroach, but have no effect on memory acquisition during conditioning. We also show that inhibition of either protein kinase A (PKA) or protein synthesis can block memory acquisition but neither has an effect on the memory once it is formed. The results suggest that sustaining memories in insects requires the persistent activity of one or more isoforms of PKC and point to a strong evolutionary conservation of the molecular mechanisms that underlie the persistence of long-term memories in the central nervous system.
Copyright © 2014 Elsevier Inc. All rights reserved.
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10 MeSH Terms
Identification of positive allosteric modulators VU0155094 (ML397) and VU0422288 (ML396) reveals new insights into the biology of metabotropic glutamate receptor 7.
Jalan-Sakrikar N, Field JR, Klar R, Mattmann ME, Gregory KJ, Zamorano R, Engers DW, Bollinger SR, Weaver CD, Days EL, Lewis LM, Utley TJ, Hurtado M, Rigault D, Acher F, Walker AG, Melancon BJ, Wood MR, Lindsley CW, Conn PJ, Xiang Z, Hopkins CR, Niswender CM
(2014) ACS Chem Neurosci 5: 1221-37
MeSH Terms: Acetanilides, Animals, Benzoates, CHO Cells, Calcium, Cricetulus, Dose-Response Relationship, Drug, Excitatory Amino Acid Agents, Excitatory Postsynaptic Potentials, G Protein-Coupled Inwardly-Rectifying Potassium Channels, Glutamic Acid, Glycine, HEK293 Cells, Hippocampus, Humans, In Vitro Techniques, Male, Mice, Inbred C57BL, Picolinic Acids, Propionates, Pyrroles, Rats, Receptors, Metabotropic Glutamate, Structure-Activity Relationship, Thallium, Transfection
Show Abstract · Added February 16, 2015
Metabotropic glutamate receptor 7 (mGlu7) is a member of the group III mGlu receptors (mGlus), encompassed by mGlu4, mGlu6, mGlu7, and mGlu8. mGlu7 is highly expressed in the presynaptic active zones of both excitatory and inhibitory synapses, and activation of the receptor regulates the release of both glutamate and GABA. mGlu7 is thought to be a relevant therapeutic target for a number of neurological and psychiatric disorders, and polymorphisms in the GRM7 gene have been linked to autism, depression, ADHD, and schizophrenia. Here we report two new pan-group III mGlu positive allosteric modulators, VU0155094 and VU0422288, which show differential activity at the various group III mGlus. Additionally, both compounds show probe dependence when assessed in the presence of distinct orthosteric agonists. By pairing studies of these nonselective compounds with a synapse in the hippocampus that expresses only mGlu7, we have validated activity of these compounds in a native tissue setting. These studies provide proof-of-concept evidence that mGlu7 activity can be modulated by positive allosteric modulation, paving the way for future therapeutics development.
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26 MeSH Terms
Characterization of statin dose response in electronic medical records.
Wei WQ, Feng Q, Jiang L, Waitara MS, Iwuchukwu OF, Roden DM, Jiang M, Xu H, Krauss RM, Rotter JI, Nickerson DA, Davis RL, Berg RL, Peissig PL, McCarty CA, Wilke RA, Denny JC
(2014) Clin Pharmacol Ther 95: 331-8
MeSH Terms: Algorithms, Alleles, Atorvastatin, Cholesterol, LDL, Cohort Studies, Databases, Factual, Dose-Response Relationship, Drug, Electronic Health Records, Genotype, Heptanoic Acids, Humans, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Hyperlipidemias, Lipid Metabolism, Lipids, Phenotype, Polymorphism, Single Nucleotide, Pyrroles, Randomized Controlled Trials as Topic, Simvastatin
Show Abstract · Added May 27, 2014
Efforts to define the genetic architecture underlying variable statin response have met with limited success, possibly because previous studies were limited to effect based on a single dose. We leveraged electronic medical records (EMRs) to extract potency (ED50) and efficacy (Emax) of statin dose-response curves and tested them for association with 144 preselected variants. Two large biobanks were used to construct dose-response curves for 2,026 and 2,252 subjects on simvastatin and atorvastatin, respectively. Atorvastatin was more efficacious, was more potent, and demonstrated less interindividual variability than simvastatin. A pharmacodynamic variant emerging from randomized trials (PRDM16) was associated with Emax for both. For atorvastatin, Emax was 51.7 mg/dl in subjects homozygous for the minor allele vs. 75.0 mg/dl for those homozygous for the major allele. We also identified several loci associated with ED50. The extraction of rigorously defined traits from EMRs for pharmacogenetic studies represents a promising approach to further understand the genetic factors contributing to drug response.
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Octahydropyrrolo[3,4-c]pyrrole negative allosteric modulators of mGlu1.
Manka JT, Rodriguez AL, Morrison RD, Venable DF, Cho HP, Blobaum AL, Daniels JS, Niswender CM, Conn PJ, Lindsley CW, Emmitte KA
(2013) Bioorg Med Chem Lett 23: 5091-6
MeSH Terms: Allosteric Regulation, Animals, Cytochrome P-450 Enzyme Inhibitors, Cytochrome P-450 Enzyme System, Dose-Response Relationship, Drug, Enzyme Inhibitors, Humans, Molecular Structure, Pyrroles, Rats, Receptors, Metabotropic Glutamate, Structure-Activity Relationship
Show Abstract · Added February 19, 2015
Development of SAR in an octahydropyrrolo[3,4-c]pyrrole series of negative allosteric modulators of mGlu1 using a functional cell-based assay is described in this Letter. The octahydropyrrolo[3,4-c]pyrrole scaffold was chosen as an isosteric replacement for the piperazine ring found in the initial hit compound. Characterization of selected compounds in protein binding assays was used to identify the most promising analogs, which were then profiled in P450 inhibition assays in order to further assess the potential for drug-likeness within this series of compounds.
Copyright © 2013 Elsevier Ltd. All rights reserved.
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12 MeSH Terms