17 results on '"McKinzie DL"'
Search Results
2. Further Characterization of Multi-Organ DEARE and Protection by 16,16 Dimethyl Prostaglandin E2 in a Mouse Model of the Hematopoietic Acute Radiation Syndrome.
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Wu T, Pelus LM, Plett PA, Sampson CH, Chua HL, Fisher A, Feng H, Liu L, Li H, Ortiz M, Chittajallu S, Luo Q, Bhatwadekar AD, Meyer TB, Zhang X, Zhou D, Fischer KD, McKinzie DL, Miller SJ, and Orschell CM
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- Female, Male, Animals, Mice, Dinoprostone pharmacology, Bone Marrow radiation effects, Disease Models, Animal, Inflammation pathology, Whole-Body Irradiation adverse effects, Mice, Inbred C57BL, Acute Radiation Syndrome drug therapy, Acute Radiation Syndrome prevention & control, Acute Radiation Syndrome etiology, Hematopoietic Stem Cell Transplantation adverse effects
- Abstract
Survivors of acute radiation exposure suffer from the delayed effects of acute radiation exposure (DEARE), a chronic condition affecting multiple organs, including lung, kidney, heart, gastrointestinal tract, eyes, and brain, and often causing cancer. While effective medical countermeasures (MCM) for the hematopoietic-acute radiation syndrome (H-ARS) have been identified and approved by the FDA, development of MCM for DEARE has not yet been successful. We previously documented residual bone marrow damage (RBMD) and progressive renal and cardiovascular DEARE in murine survivors of H-ARS, and significant survival efficacy of 16,16-dimethyl prostaglandin E2 (dmPGE2) given as a radioprotectant or radiomitigator for H-ARS. We now describe additional DEARE (physiological and neural function, progressive fur graying, ocular inflammation, and malignancy) developing after sub-threshold doses in our H-ARS model, and detailed analysis of the effects of dmPGE2 administered before (PGE-pre) or after (PGE-post) lethal total-body irradiation (TBI) on these DEARE. Administration of PGE-pre normalized the twofold reduction of white blood cells (WBC) and lymphocytes seen in vehicle-treated survivors (Veh), and increased the number of bone marrow (BM) cells, splenocytes, thymocytes, and phenotypically defined hematopoietic progenitor cells (HPC) and hematopoietic stem cells (HSC) to levels equivalent to those in non-irradiated age-matched controls. PGE-pre significantly protected HPC colony formation ex vivo by >twofold, long term-HSC in vivo engraftment potential up to ninefold, and significantly blunted TBI-induced myeloid skewing. Secondary transplantation documented continued production of LT-HSC with normal lineage differentiation. PGE-pre reduced development of DEARE cardiovascular pathologies and renal damage; prevented coronary artery rarefication, blunted progressive loss of coronary artery endothelia, reduced inflammation and coronary early senescence, and blunted radiation-induced increase in blood urea nitrogen (BUN). Ocular monocytes were significantly lower in PGE-pre mice, as was TBI-induced fur graying. Increased body weight and decreased frailty in male mice, and reduced incidence of thymic lymphoma were documented in PGE-pre mice. In assays measuring behavioral and cognitive functions, PGE-pre reduced anxiety in females, significantly blunted shock flinch response, and increased exploratory behavior in males. No effect of TBI was observed on memory in any group. PGE-post, despite significantly increasing 30-day survival in H-ARS and WBC and hematopoietic recovery, was not effective in reducing TBI-induced RBMD or any other DEARE. In summary, dmPGE2 administered as an H-ARS MCM before lethal TBI significantly increased 30-day survival and ameliorated RBMD and multi-organ and cognitive/behavioral DEARE to at least 12 months after TBI, whereas given after TBI, dmPGE2 enhances survival from H-ARS but has little impact on RBMD or other DEARE., (©2023 by Radiation Research Society. All rights of reproduction in any form reserved.)
- Published
- 2023
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3. Microglial knockdown does not affect acute withdrawal but delays analgesic tolerance from oxycodone in male and female C57BL/6J mice.
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El Jordi O, Fischer KD, Meyer TB, Atwood BK, Oblak AL, Pan RW, and McKinzie DL
- Abstract
Opioid Use Disorder (OUD) affects approximately 8%-12% of the population. In dependent individuals, abrupt cessation of opioid taking results in adverse withdrawal symptoms that reinforce drug taking behavior. Considerable unmet clinical need exists for new pharmacotherapies to treat opioid withdrawal as well as improve long-term abstinence. The neuroimmune system has received much scientific attention in recent years as a potential therapeutic target to combat various neurodegenerative and psychiatric disorders including addiction. However, the specific contribution of microglia has not been investigated in oxycodone dependence. Chronic daily treatment with the CSF1R inhibitor Pexidartinib (PLX3397) was administered to knockdown microglia expression and evaluate consequences on analgesia and on naloxone induced withdrawal from oxycodone. In vivo results indicated that an approximately 40% reduction in brain IBA1 staining was achieved in the PLX treatment group, which was associated with a delay in the development of analgesic tolerance to oxycodone and maintained antinociceptive efficacy. Acute withdrawal behavioral symptoms, brain astrocyte expression, and levels of many neuroinflammatory markers were not affected by PLX treatment. KC/GRO (also known as CXCL1) was significantly enhanced in the somatosensory cortex in oxycodone-treated mice receiving PLX. Microglial knock-down did not affect the expression of naloxoneinduced opioid withdrawal but affected antinociceptive responsivity. The consequences of increased KC/GRO expression within the somatosensory cortex due to microglial reduction during opioid dependence are unclear but may be important for neural pathways mediating opioid-induced analgesia., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 El Jordi, Fischer, Meyer, Atwood, Oblak, Pan and McKinzie.)
- Published
- 2022
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4. Bassoon contributes to tau-seed propagation and neurotoxicity.
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Martinez P, Patel H, You Y, Jury N, Perkins A, Lee-Gosselin A, Taylor X, You Y, Viana Di Prisco G, Huang X, Dutta S, Wijeratne AB, Redding-Ochoa J, Shahid SS, Codocedo JF, Min S, Landreth GE, Mosley AL, Wu YC, McKinzie DL, Rochet JC, Zhang J, Atwood BK, Troncoso J, and Lasagna-Reeves CA
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- Animals, Mice, tau Proteins metabolism, Proteomics, Brain metabolism, Alzheimer Disease metabolism, Tauopathies metabolism
- Abstract
Tau aggregation is a defining histopathological feature of Alzheimer's disease and other tauopathies. However, the cellular mechanisms involved in tau propagation remain unclear. Here, we performed an unbiased quantitative proteomic study to identify proteins that specifically interact with this tau seed. We identified Bassoon (BSN), a presynaptic scaffolding protein, as an interactor of the tau seed isolated from a mouse model of tauopathy, and from Alzheimer's disease and progressive supranuclear palsy postmortem samples. We show that BSN exacerbates tau seeding and toxicity in both mouse and Drosophila models for tauopathy, and that BSN downregulation decreases tau spreading and overall disease pathology, rescuing synaptic and behavioral impairments and reducing brain atrophy. Our findings improve the understanding of how tau seeds can be stabilized by interactors such as BSN. Inhibiting tau-seed interactions is a potential new therapeutic approach for neurodegenerative tauopathies., (© 2022. The Author(s).)
- Published
- 2022
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5. Robust Pharmacodynamic Effect of LY3202626, a Central Nervous System Penetrant, Low Dose BACE1 Inhibitor, in Humans and Nonclinical Species.
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Willis BA, Lowe SL, Monk SA, Cocke PJ, Aluise CD, Boggs LN, Borders AR, Brier RA, Dean RA, Green SJ, James DE, Jhee SS, Lin Q, Lo AC, May PC, Watson BM, Winneroski LL, Yang Z, Zimmer JA, McKinzie DL, and Mergott DJ
- Abstract
Background: The development of beta-site amyloid-beta precursor protein cleaving enzyme (BACE) 1 inhibitors for the treatment of Alzheimer's disease requires optimization of inhibitor potency, selectivity, and brain penetration. Moreover, there is a need for low-dose compounds since liver toxicity was found with some BACE inhibitors., Objective: To determine whether the high in vitro potency and robust pharmacodynamic effect of the BACE inhibitor LY3202626 observed in nonclinical species translated to humans., Methods: The effect of LY3202626 versus vehicle on amyloid-β (Aβ) levels was evaluated in a series of in vitro assays, as well as in in vivo and multi-part clinical pharmacology studies. Aβ levels were measured using analytical biochemistry assays in brain, plasma, and cerebrospinal fluid (CSF) of mice, dogs and humans. Nonclinical data were analyzed using an ANOVA followed by Tukey's post hoc test and clinical data used summary statistics., Results: LY3202626 exhibited significant human BACE1 inhibition, with an IC
50 of 0.615±0.101 nM in a fluorescence resonance energy transfer assay and an EC50 of 0.275±0.176 nM for lowering Aβ1-40 and 0.228±0.244 nM for Aβ1-42 in PDAPP neuronal cultures. In dogs, CSF Aβ1hboxx concentrations were significantly reduced by ∼80% at 9 hours following a 1.5 mg/kg dose. In humans, CSF Aβ1-42 was reduced by 73.1±7.96 % following administration of 6 mg QD. LY3202626 was found to freely cross the blood-brain barrier in dogs and humans., Conclusion: LY3202626 is a potent BACE1 inhibitor with high blood-brain barrier permeability. The favorable safety and pharmacokinetic/pharmacodynamic profile of LY3202626 supports further clinical development., Competing Interests: BAW, SLL, SAM, PJC, CDA, LNB, ARB, RAB, RAD, SJG, DEJ, QL, ACL, PCM, BMW, LLW, ZY, JAZ, DLM, DJM are all employed by and minor stockholders in Eli Lilly and Company or were at the time these studies were conducted., (© 2022 – The authors. Published by IOS Press.)- Published
- 2022
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6. Discovery and Early Clinical Development of LY3202626, a Low-Dose, CNS-Penetrant BACE Inhibitor.
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McKinzie DL, Winneroski LL, Green SJ, Hembre EJ, Erickson JA, Willis BA, Monk SA, Aluise CD, Baker TK, Lopez JE, Hendle J, Beck JP, Brier RA, Boggs LN, Borders AR, Cocke PJ, Garcia-Losada P, Lowe SL, Mathes BM, May PC, Porter WJ, Stout SL, Timm DE, Watson BM, Yang Z, and Mergott DJ
- Subjects
- Amyloid Precursor Protein Secretases metabolism, Animals, Aspartic Acid Endopeptidases metabolism, Blood-Brain Barrier physiology, Brain metabolism, Crystallography, X-Ray, Dogs, Drug Stability, Heterocyclic Compounds, 2-Ring chemical synthesis, Heterocyclic Compounds, 2-Ring pharmacokinetics, Humans, Madin Darby Canine Kidney Cells, Male, Mice, Microsomes, Liver metabolism, Molecular Structure, Protease Inhibitors chemical synthesis, Protease Inhibitors metabolism, Protease Inhibitors pharmacokinetics, Protein Binding, Pyrazines chemical synthesis, Pyrazines pharmacokinetics, Pyrroles chemical synthesis, Pyrroles pharmacokinetics, Rats, Structure-Activity Relationship, Amyloid Precursor Protein Secretases antagonists & inhibitors, Aspartic Acid Endopeptidases antagonists & inhibitors, Heterocyclic Compounds, 2-Ring pharmacology, Protease Inhibitors pharmacology, Pyrazines pharmacology, Pyrroles pharmacology
- Abstract
The beta-site APP cleaving enzyme 1, known as BACE1, has been a widely pursued Alzheimer's disease drug target owing to its critical role in the production of amyloid-beta. We have previously reported the clinical development of LY2811376 and LY2886721. LY2811376 advanced to Phase I before development was terminated due to nonclinical retinal toxicity. LY2886721 advanced to Phase II, but development was halted due to abnormally elevated liver enzymes. Herein, we report the discovery and clinical development of LY3202626, a highly potent, CNS-penetrant, and low-dose BACE inhibitor, which successfully addressed these key development challenges.
- Published
- 2021
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7. Genetic Background and Sex: Impact on Generalizability of Research Findings in Pharmacology Studies.
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Sukoff Rizzo SJ, McTighe S, and McKinzie DL
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- Animals, Humans, Models, Animal, Mutation, Pharmacology, Clinical, Reproducibility of Results, Genetic Background, Genome
- Abstract
Animal models consisting of inbred laboratory rodent strains have been a powerful tool for decades, helping to unravel the underpinnings of biological problems and employed to evaluate potential therapeutic treatments in drug discovery. While inbred strains demonstrate relatively reliable and predictable responses, using a single inbred strain alone or as a background to a mutation is analogous to running a clinical trial in a single individual and their identical twins. Indeed, complex etiologies drive the most common human diseases, and a single inbred strain that is a surrogate of a single genome, or data generated from a single sex, is not representative of the genetically diverse patient populations. Further, pharmacological and toxicology data generated in otherwise healthy animals may not translate to disease states where physiology, metabolism, and general health are compromised. The purpose of this chapter is to provide guidance for improving generalizability of preclinical studies by providing insight into necessary considerations for introducing systematic variation within the study design, such as genetic diversity, the use of both sexes, and selection of appropriate age and disease model. The outcome of implementing these considerations should be that reproducibility and generalizability of significant results are significantly enhanced leading to improved clinical translation.
- Published
- 2020
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8. Chronic pain impairs cognitive flexibility and engages novel learning strategies in rats.
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Cowen SL, Phelps CE, Navratilova E, McKinzie DL, Okun A, Husain O, Gleason SD, Witkin JM, and Porreca F
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- Animals, Chronic Pain etiology, Decision Making physiology, Male, Peripheral Nerve Injuries complications, Peripheral Nerve Injuries psychology, Rats, Rats, Sprague-Dawley, Chronic Pain psychology, Cognition physiology, Executive Function physiology, Learning physiology
- Abstract
Cognitive flexibility, the ability to adapt behavior to changing outcomes, is critical to survival. The prefrontal cortex is a key site of cognitive control, and chronic pain is known to lead to significant morphological changes to this brain region. Nevertheless, the effects of chronic pain on cognitive flexibility and learning remain uncertain. We used an instrumental paradigm to assess adaptive learning in an experimental model of chronic pain induced by tight ligation of the spinal nerves L5/6 (spinal nerve ligation model). Naive, sham-operated, and spinal nerve ligation (SNL) rats were trained to perform fixed-ratio, variable-ratio, and contingency-shift behaviors for food reward. Although all groups learned an initial lever-reward contingency, learning was slower in SNL animals in a subsequent choice task that reversed reinforcement contingencies. Temporal analysis of lever-press responses across sessions indicated no apparent deficits in memory consolidation or retrieval. However, analysis of learning within sessions revealed that the lever presses of SNL animals occurred in bursts, followed by delays. Unexpectedly, the degree of bursting correlated positively with learning. Under a variable-ratio probabilistic task, SNL rats chose a less profitable behavioral strategy compared with naive and sham-operated animals. After extinction of behavior for learned preferences, SNL animals reverted to their initially preferred (ie, less profitable) behavioral choice. Our data suggest that in the face of uncertainty, chronic pain drives a preference for familiar associations, consistent with reduced cognitive flexibility. The observed burst-like responding may represent a novel learning strategy in animals with chronic pain.
- Published
- 2018
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9. Synthesis and Pharmacological Characterization of C4 β -Amide-Substituted 2-Aminobicyclo[3.1.0]hexane-2,6-dicarboxylates. Identification of (1 S,2 S,4 S,5 R,6 S)-2-Amino-4-[(3-methoxybenzoyl)amino]bicyclo[3.1.0]hexane-2,6-dicarboxylic Acid (LY2794193), a Highly Potent and Selective mGlu 3 Receptor Agonist.
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Monn JA, Henry SS, Massey SM, Clawson DK, Chen Q, Diseroad BA, Bhardwaj RM, Atwell S, Lu F, Wang J, Russell M, Heinz BA, Wang XS, Carter JH, Getman BG, Adragni K, Broad LM, Sanger HE, Ursu D, Catlow JT, Swanson S, Johnson BG, Shaw DB, McKinzie DL, and Hao J
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- Animals, Bridged Bicyclo Compounds pharmacokinetics, Crystallography, X-Ray, Cyclic AMP pharmacology, Excitatory Amino Acid Agonists pharmacokinetics, Excitatory Amino Acid Antagonists pharmacology, Humans, Male, Models, Molecular, Molecular Docking Simulation, Molecular Structure, Motor Activity drug effects, Neurons drug effects, Neurons metabolism, Phencyclidine antagonists & inhibitors, Phencyclidine pharmacology, Protein Binding, Rats, Rats, Sprague-Dawley, Bridged Bicyclo Compounds chemical synthesis, Bridged Bicyclo Compounds pharmacology, Excitatory Amino Acid Agonists chemical synthesis, Excitatory Amino Acid Agonists pharmacology, Receptors, Metabotropic Glutamate agonists
- Abstract
Multiple therapeutic opportunities have been suggested for compounds capable of selective activation of metabotropic glutamate 3 (mGlu
3 ) receptors, but small molecule tools are lacking. As part of our ongoing efforts to identify potent, selective, and systemically bioavailable agonists for mGlu2 and mGlu3 receptor subtypes, a series of C4β -N-linked variants of (1 S,2 S,5 R,6 S)-2-amino-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid 1 (LY354740) were prepared and evaluated for both mGlu2 and mGlu3 receptor binding affinity and functional cellular responses. From this investigation we identified (1 S,2 S,4 S,5 R,6 S)-2-amino-4-[(3-methoxybenzoyl)amino]bicyclo[3.1.0]hexane-2,6-dicarboxylic acid 8p (LY2794193), a molecule that demonstrates remarkable mGlu3 receptor selectivity. Crystallization of 8p with the amino terminal domain of hmGlu3 revealed critical binding interactions for this ligand with residues adjacent to the glutamate binding site, while pharmacokinetic assessment of 8p combined with its effect in an mGlu2 receptor-dependent behavioral model provides estimates for doses of this compound that would be expected to selectively engage and activate central mGlu3 receptors in vivo.- Published
- 2018
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10. Translational Pharmacology of the Metabotropic Glutamate 2 Receptor-Preferring Agonist LY2812223 in the Animal and Human Brain.
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Felder CC, Schober DA, Tu Y, Quets A, Xiao H, Watt M, Siuda E, Nisenbaum E, Xiang C, Heinz B, Prieto L, McKinzie DL, and Monn JA
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- Animals, Brain metabolism, Bridged Bicyclo Compounds metabolism, Dose-Response Relationship, Drug, Excitatory Amino Acid Agonists metabolism, Humans, Mice, Mice, Knockout, Protein Binding drug effects, Protein Binding physiology, Rats, Rats, Sprague-Dawley, Receptors, Metabotropic Glutamate metabolism, Translational Research, Biomedical, Triazoles metabolism, Brain drug effects, Bridged Bicyclo Compounds pharmacology, Drug Partial Agonism, Excitatory Amino Acid Agonists pharmacology, Receptors, Metabotropic Glutamate agonists, Triazoles pharmacology
- Abstract
LY2812223 [(1 R ,2 S ,4 R ,5 R ,6 R )-2-amino-4-(1 H -1,2,4-triazol-3-ylsulfanyl)bicyclo[3.1.0]hexane-2,6-dicarboxylic acid] was identified via structure-activity studies arising from the potent metabotropic glutamate mGlu2/3 receptor agonist LY354740 [(+)-2-aminobicyclo[3.1.0] hexane-2,6-dicarboxylic acid] as an mGlu2-preferring agonist. This pharmacology was determined using stably transfected cells containing either the human mGlu2 or mGlu3 receptor. We extended the pharmacological evaluation of LY2812223 to native brain tissues derived from relevant species used for preclinical drug development as well as human postmortem brain tissue. This analysis was conducted to ensure pharmacological translation from animals to human subjects in subsequent clinical studies. A guanosine 5'- O -(3-[
35 S]thio)triphosphate (GTP γ S) functional binding assay, a method for measuring Gi -coupled signaling that is inherent to the group 2 mGlu receptors, was used to evaluate LY2812223 pharmacology of native mGlu receptors in mouse, rat, nonhuman primate, and human cortical brain tissue samples. In native tissue membranes, LY2812223 unexpectedly acted as a partial agonist across all species tested. Activity of LY2812223 was lost in cortical membranes collected from mGlu2 knockout mice, but not those from mGlu3 knockout mice, providing additional support for mGlu2-preferring activity. Other signal transduction assays were used for comparison with the GTP binding assay (cAMP, calcium mobilization, and dynamic mass redistribution). In ectopic cell line-based assays, LY2812223 displayed near maximal agonist responses at the mGlu2 receptor across all assay formats, while it showed no functional agonist activity at the mGlu3 receptor except in the cAMP assay. In native brain slices or membranes that express both mGlu2 and mGlu3 receptors, LY2812223 displayed unexpected partial agonist activity, which may suggest a functional interplay between these receptor subtypes in the brain., (Copyright © 2017 by The American Society for Pharmacology and Experimental Therapeutics.)- Published
- 2017
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11. Hedonic and motivational responses to food reward are unchanged in rats with neuropathic pain.
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Okun A, McKinzie DL, Witkin JM, Remeniuk B, Husein O, Gleason SD, Oyarzo J, Navratilova E, McElroy B, Cowen S, Kennedy JD, and Porreca F
- Subjects
- Animals, Conditioning, Operant drug effects, Conditioning, Operant physiology, Disease Models, Animal, Extinction, Psychological physiology, Freund's Adjuvant toxicity, Male, Neuralgia etiology, Pain Measurement, Rats, Rats, Sprague-Dawley, Spinal Nerves injuries, Sucrose administration & dosage, Taste drug effects, Time Factors, Food, Motivation physiology, Neuralgia physiopathology, Neuralgia psychology, Reward
- Abstract
Rewards influence responses to acute painful stimuli, but the relationship of chronic pain to hedonic or motivational aspects of reward is not well understood. We independently evaluated hedonic qualities of sweet or bitter tastants and motivation to seek food reward in rats with experimental neuropathic pain induced by L5/6 spinal nerve ligation. Hedonic response was measured by implantation of intraoral catheters to allow passive delivery of liquid solutions, and "liking/disliking" responses were scored according to a facial reactivity scale. Spinal nerve ligation rats did not differ from controls in either "liking" or "disliking" reactions to intraoral sucrose or quinine, respectively, at postsurgery day 21, suggesting no differences in perceived hedonic value of sweet or bitter tastants. To assess possible motivational deficits during acute and chronic pain, we used fixed- and progressive-ratio response paradigms of sucrose pellet presentation in rats with transient inflammatory or chronic neuropathic pain. Assessment of response acquisition and break points under the progressive ratio schedule revealed no differences between sham and spinal nerve ligation rats for up to 120 days after injury. However, rats with inflammation showed decrements in lever pressing and break points on days 1 and 2 after complete Freund adjuvant injection that normalized by day 4, consistent with transient ongoing pain. Thus, although acute ongoing inflammatory pain may transiently reduce reward motivation, we did not detect influences of chronic neuropathic pain on hedonic or motivational responses to food rewards. Adaptations that allow normal reward responding to food regardless of chronic pain may be of evolutionary benefit to promote survival., Competing Interests: We have no conflicts of interest to declare.
- Published
- 2016
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12. Preclinical findings predicting efficacy and side-effect profile of LY2940094, an antagonist of nociceptin receptors.
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Witkin JM, Rorick-Kehn LM, Benvenga MJ, Adams BL, Gleason SD, Knitowski KM, Li X, Chaney S, Falcone JF, Smith JW, Foss J, Lloyd K, Catlow JT, McKinzie DL, Svensson KA, Barth VN, Toledo MA, Diaz N, Lafuente C, Jiménez A, Benito A, Pedregal C, Martínez-Grau MA, Post A, Ansonoff MA, Pintar JE, and Statnick MA
- Abstract
Nociceptin/Orphanin FQ (N/OFQ) is a 17 amino acid peptide whose receptor is designated ORL1 or nociceptin receptor (NOP). We utilized a potent, selective, and orally bioavailable antagonist with documented engagement with NOP receptors in vivo to assess antidepressant- and anxiolytic-related pharmacological effects of NOP receptor blockade along with measures of cognitive and motor impingement. LY2940094 ([2-[4-[(2-chloro-4,4-difluoro-spiro[5H-thieno[2,3-c]pyran-7,4'-piperidine]-1'-yl)methyl]-3-methyl-pyrazol-1-yl]-3-pyridyl]methanol) displayed antidepressant-like behavioral effects in the forced-swim test in mice, an effect absent in NOP
-/- mice. LY2940094 also augmented the behavioral effect of fluoxetine without changing target occupancies (NOP and serotonin reuptake transporter [SERT]). LY2940094 did not have effects under a differential-reinforcement of low rate schedule. Although anxiolytic-like effects were not observed in some animal models (conditioned suppression, 4-plate test, novelty-suppressed feeding), LY2940094 had effects like that of anxiolytic drugs in three assays: fear-conditioned freezing in mice, stress-induced increases in cerebellar cGMP in mice, and stress-induced hyperthermia in rats. These are the first reports of anxiolytic-like activity with a systemically viable NOP receptor antagonist. LY2940094 did not disrupt performance in either a 5-choice serial reaction time or delayed matching-to-position assay. LY2940094 was also not an activator or suppressor of locomotion in rodents nor did it induce failures of rotarod performance. These data suggest that LY2940094 has unique antidepressant- and anxiolytic-related pharmacological effects in rodents. Clinical proof of concept data on this molecule in depressed patients have been reported elsewhere.- Published
- 2016
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13. Exploratory analysis for a targeted patient population responsive to the metabotropic glutamate 2/3 receptor agonist pomaglumetad methionil in schizophrenia.
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Kinon BJ, Millen BA, Zhang L, and McKinzie DL
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- Adolescent, Adult, Aged, Dose-Response Relationship, Drug, Double-Blind Method, Female, Humans, Male, Middle Aged, Psychiatric Status Rating Scales, Randomized Controlled Trials as Topic, Treatment Outcome, Young Adult, Antipsychotic Agents therapeutic use, Bridged Bicyclo Compounds, Heterocyclic therapeutic use, Cyclic S-Oxides therapeutic use, Receptors, Metabotropic Glutamate agonists, Schizophrenia drug therapy
- Abstract
Background: Accumulating evidence indicates that glutamatergic tone in schizophrenia may vary as a function of illness duration or medication history. We conducted an exploratory analysis of the existing clinical trial database of pomaglumetad methionil (pomaglumetad) to demonstrate treatment response in targeted patient populations., Methods: Results of the H8Y-MC-HBBM (HBBM) study and an integrated analysis based on five placebo-controlled trials were summarized. Patients with schizophrenia were randomly assigned to receive either pomaglumetad, 40 or 80 mg twice daily (BID), placebo, or risperidone, 2 mg BID, for up to 6 weeks. Patient subgroups were analyzed to determine the efficacy of pomaglumetad treatment in patients early-in-disease (≤3 years) and late-in-disease (≥10 years) (HBBM, 40 mg, n = 206, 80 mg, n = 198; integrated analysis, 40 mg, n = 382, 80 mg, n = 381) and in patients previously treated with central nervous system drugs with prominent serotonin 2A receptor antagonist activity (S2 group) or with predominant dopamine D2 receptor antagonist activity (D2 group; HBBM, 40 mg, n = 275, 80 mg, n = 269; integrated analysis, 40 mg, n = 590, 80 mg, n = 506)., Results: In the HBBM study and integrated analysis, only patients early-in-disease or previously treated with D2 drugs exhibited significantly greater improvement relative to those receiving placebo, when treated with pomaglumetad, 40 mg (but not 80 mg) BID. Treatment response to risperidone did not appear to depend upon these patient subgroups., Conclusions: Demonstration of antipsychotic efficacy of a potential glutamate-based pharmacotherapy for schizophrenia may require the identification of appropriate patient subgroups whose treatment responsiveness may be fundamentally related to dysregulation of central nervous system glutamatergic tone., (Copyright © 2015 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)
- Published
- 2015
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14. Design and synthesis of N-[6-(Substituted Aminoethylideneamino)-2-Hydroxyindan-1-yl]arylamides as selective and potent muscarinic M₁ agonists.
- Author
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Liu B, Croy CH, Hitchcock SA, Allen JR, Rao Z, Evans D, Bures MG, McKinzie DL, Watt ML, Stuart Gregory G, Hansen MM, Hoogestraat PJ, Jamison JA, Okha-Mokube FM, Stratford RE, Turner W, Bymaster F, and Felder CC
- Subjects
- Amides chemical synthesis, Animals, Dose-Response Relationship, Drug, Humans, Molecular Structure, Rats, Structure-Activity Relationship, Amides chemistry, Amides pharmacology, Drug Design, Receptor, Muscarinic M1 agonists
- Abstract
The observation that cholinergic deafferentation of circuits projecting from forebrain basal nuclei to frontal and hippocampal circuits occurs in Alzheimer's disease has led to drug-targeting of muscarinic M1 receptors to alleviate cognitive symptoms. The high homology within the acetylcholine binding domain of this family however has made receptor-selective ligand development challenging. This work presents the synthesis scheme, pharmacokinetic and structure-activity-relationship study findings for M1-selective ligand, LY593093. Pharmacologically the compound acts as an orthosteric ligand. The homology modeling work presented however will illustrate that compound binding spans from the acetylcholine pocket to the extracellular loops of the receptor, a common allosteric vestibule for the muscarinic protein family. Altogether LY593093 represents a growing class of multi-topic ligands which interact with the receptors in both the ortho- and allosteric binding sites, but which exert their activation mechanism as an orthosteric ligand., (Copyright © 2015. Published by Elsevier Ltd.)
- Published
- 2015
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15. Synthesis and Pharmacological Characterization of C4-(Thiotriazolyl)-substituted-2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylates. Identification of (1R,2S,4R,5R,6R)-2-Amino-4-(1H-1,2,4-triazol-3-ylsulfanyl)bicyclo[3.1.0]hexane-2,6-dicarboxylic Acid (LY2812223), a Highly Potent, Functionally Selective mGlu2 Receptor Agonist.
- Author
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Monn JA, Prieto L, Taboada L, Hao J, Reinhard MR, Henry SS, Beadle CD, Walton L, Man T, Rudyk H, Clark B, Tupper D, Baker SR, Lamas C, Montero C, Marcos A, Blanco J, Bures M, Clawson DK, Atwell S, Lu F, Wang J, Russell M, Heinz BA, Wang X, Carter JH, Getman BG, Catlow JT, Swanson S, Johnson BG, Shaw DB, and McKinzie DL
- Subjects
- Allosteric Regulation, Animals, Binding, Competitive, Bridged Bicyclo Compounds pharmacokinetics, Bridged Bicyclo Compounds pharmacology, Calcium metabolism, Cyclic AMP metabolism, Dogs, Drug Partial Agonism, Humans, Male, Mice, Models, Molecular, Motor Activity drug effects, Mutagenesis, Site-Directed, Protein Structure, Tertiary, Rats, Sprague-Dawley, Receptors, Metabotropic Glutamate antagonists & inhibitors, Receptors, Metabotropic Glutamate genetics, Receptors, Metabotropic Glutamate metabolism, Stereoisomerism, Triazoles pharmacokinetics, Triazoles pharmacology, Bridged Bicyclo Compounds chemistry, Receptors, Metabotropic Glutamate agonists, Triazoles chemistry
- Abstract
Identification of orthosteric mGlu(2/3) receptor agonists capable of discriminating between individual mGlu2 and mGlu3 subtypes has been highly challenging owing to the glutamate-site sequence homology between these proteins. Herein we detail the preparation and characterization of a series of molecules related to (1S,2S,5R,6S)-2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylate 1 (LY354740) bearing C4-thiotriazole substituents. On the basis of second messenger responses in cells expressing other recombinant human mGlu2/3 subtypes, a number of high potency and efficacy mGlu2 receptor agonists exhibiting low potency mGlu3 partial agonist/antagonist activity were identified. From this, (1R,2S,4R,5R,6R)-2-amino-4-(1H-1,2,4-triazol-3-ylsulfanyl)bicyclo[3.1.0]hexane-2,6-dicarboxylic acid 14a (LY2812223) was further characterized. Cocrystallization of 14a with the amino terminal domains of hmGlu2 and hmGlu3 combined with site-directed mutation studies has clarified the underlying molecular basis of this unique pharmacology. Evaluation of 14a in a rat model responsive to mGlu2 receptor activation coupled with a measure of central drug disposition provides evidence that this molecule engages and activates central mGlu2 receptors in vivo.
- Published
- 2015
- Full Text
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16. Synthesis and pharmacological characterization of C4-disubstituted analogs of 1S,2S,5R,6S-2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylate: identification of a potent, selective metabotropic glutamate receptor agonist and determination of agonist-bound human mGlu2 and mGlu3 amino terminal domain structures.
- Author
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Monn JA, Prieto L, Taboada L, Pedregal C, Hao J, Reinhard MR, Henry SS, Goldsmith PJ, Beadle CD, Walton L, Man T, Rudyk H, Clark B, Tupper D, Baker SR, Lamas C, Montero C, Marcos A, Blanco J, Bures M, Clawson DK, Atwell S, Lu F, Wang J, Russell M, Heinz BA, Wang X, Carter JH, Xiang C, Catlow JT, Swanson S, Sanger H, Broad LM, Johnson MP, Knopp KL, Simmons RM, Johnson BG, Shaw DB, and McKinzie DL
- Subjects
- Animals, Bridged Bicyclo Compounds chemistry, Bridged Bicyclo Compounds metabolism, Crystallography, X-Ray, Humans, Male, Models, Molecular, Protein Structure, Tertiary, Rats, Rats, Sprague-Dawley, Receptors, Metabotropic Glutamate chemistry, Receptors, Metabotropic Glutamate genetics, Spiro Compounds chemistry, Spiro Compounds metabolism, Bridged Bicyclo Compounds pharmacology, Receptors, Metabotropic Glutamate agonists, Spiro Compounds pharmacology
- Abstract
As part of our ongoing research to identify novel agents acting at metabotropic glutamate 2 (mGlu2) and 3 (mGlu3) receptors, we have previously reported the identification of the C4α-methyl analog of mGlu2/3 receptor agonist 1 (LY354740). This molecule, 1S,2S,4R,5R,6S-2-amino-4-methylbicyclo[3.1.0]hexane-2,6-dicarboxylate 2 (LY541850), exhibited an unexpected mGlu2 agonist/mGlu3 antagonist pharmacological profile, whereas the C4β-methyl diastereomer (3) possessed dual mGlu2/3 receptor agonist activity. We have now further explored this structure-activity relationship through the preparation of cyclic and acyclic C4-disubstituted analogs of 1, leading to the identification of C4-spirocyclopropane 5 (LY2934747), a novel, potent, and systemically bioavailable mGlu2/3 receptor agonist which exhibits both antipsychotic and analgesic properties in vivo. In addition, through the combined use of protein-ligand X-ray crystallography employing recombinant human mGlu2/3 receptor amino terminal domains, molecular modeling, and site-directed mutagenesis, a molecular basis for the observed pharmacological profile of compound 2 is proposed.
- Published
- 2015
- Full Text
- View/download PDF
17. Determining pharmacological selectivity of the kappa opioid receptor antagonist LY2456302 using pupillometry as a translational biomarker in rat and human.
- Author
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Rorick-Kehn LM, Witcher JW, Lowe SL, Gonzales CR, Weller MA, Bell RL, Hart JC, Need AB, McKinzie JH, Statnick MA, Suico JG, McKinzie DL, Tauscher-Wisniewski S, Mitch CH, Stoltz RR, and Wong CJ
- Subjects
- Adolescent, Adult, Animals, Benzamides blood, Cross-Over Studies, Dose-Response Relationship, Drug, Double-Blind Method, Fentanyl pharmacology, Humans, Male, Middle Aged, Miosis chemically induced, Miosis drug therapy, Morphine pharmacology, Mydriasis chemically induced, Mydriasis drug therapy, Naltrexone pharmacology, Narcotic Antagonists blood, Narcotics pharmacology, Pupil physiology, Pyrrolidines blood, Rats, Sprague-Dawley, Receptors, Opioid, kappa agonists, Receptors, Opioid, kappa metabolism, Young Adult, Benzamides pharmacology, Narcotic Antagonists pharmacology, Pupil drug effects, Pyrrolidines pharmacology, Receptors, Opioid, kappa antagonists & inhibitors
- Abstract
Background: Selective kappa opioid receptor antagonism is a promising experimental strategy for the treatment of depression. The kappa opioid receptor antagonist, LY2456302, exhibits ~30-fold higher affinity for kappa opioid receptors over mu opioid receptors, which is the next closest identified pharmacology., Methods: Here, we determined kappa opioid receptor pharmacological selectivity of LY2456302 by assessing mu opioid receptor antagonism using translational pupillometry in rats and humans., Results: In rats, morphine-induced mydriasis was completely blocked by the nonselective opioid receptor antagonist naloxone (3mg/kg, which produced 90% mu opioid receptor occupancy), while 100 and 300 mg/kg LY2456302 (which produced 56% and 87% mu opioid receptor occupancy, respectively) only partially blocked morphine-induced mydriasis. In humans, fentanyl-induced miosis was completely blocked by 50mg naltrexone, and LY2456302 dose-dependently blocked miosis at 25 and 60 mg (minimal-to-no blockade at 4-10mg)., Conclusions: We demonstrate, for the first time, the use of translational pupillometry in the context of receptor occupancy to identify a clinical dose of LY2456302 achieving maximal kappa opioid receptor occupancy without evidence of significant mu receptor antagonism., (© The Author 2015. Published by Oxford University Press on behalf of CINP.)
- Published
- 2014
- Full Text
- View/download PDF
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