20 results on '"Engers, Darren W."'
Search Results
2. Discovery of an Orally Bioavailable and Central Nervous System (CNS) Penetrant mGlu(7) Negative Allosteric Modulator (NAM) in Vivo Tool Compound: N-(2-(1H-1,2,4-triazol-1-yl)-5-(trifluoromethoxy)phenyl)-4-(cyclopropylmethoxy)-3-methoxybenzamide (VU6012962)
- Author
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Reed, Carson W., Yohn, Samantha E., Washecheck, Jordan P., Roenfanz, Hanna F., Quitalig, Marc C., Luscombe, Vincent B., Jenkins, Matthew T., Rodriguez, Alice L., Engers, Darren W., Blobaum, Anna L., Conn, P. Jeffrey, Niswender, Colleen M., and Lindsley, Craig W.
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Male ,Molecular Structure ,Brain ,Triazoles ,Receptors, Metabotropic Glutamate ,Article ,Mice, Inbred C57BL ,Rats, Sprague-Dawley ,Structure-Activity Relationship ,Allosteric Regulation ,Anti-Anxiety Agents ,Benzamides ,Drug Discovery ,Animals - Abstract
Herein, we report the discovery of a new, orally bioavailable and CNS-penetrant metabotropic glutamate receptor 7 (mGlu(7)) negative allosteric modulator (NAM) that achieves exposure in cerebral spinal fluid (CSF) 2.5× above the in vitro IC(50) at minimum effective doses (MEDs) of 3 mg/kg in preclinical anxiety models.
- Published
- 2019
3. Discovery of VU2957 (Valiglurax): An mGlu4 Positive Allosteric Modulator Evaluated as a Preclinical Candidate for the Treatment of Parkinson's Disease.
- Author
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Panarese, Joseph D., Engers, Darren W., Wu, Yong-Jin, Bronson, Joanne J., Macor, John E., Chun, Aspen, Rodriguez, Alice L., Felts, Andrew S., Engers, Julie L., Loch, Matthew T., Emmitte, Kyle A., Castelhano, Arlindo L., Kates, Michael J., Nader, Michael A., Jones, Carrie K., Blobaum, Anna L., Conn, P. Jeffrey, Niswender, Colleen M., Hopkins, Corey R., and Lindsley, Craig W.
- Published
- 2019
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4. Activation of Metabotropic Glutamate Receptor 7 Is Required for Induction of Long-Term Potentiation at SCCA1 Synapses in the Hippocampus.
- Author
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Klar, Rebecca, Walker, Adam G., Ghose, Dipanwita, Grueter, Brad A., Engers, Darren W., Hopkins, Corey R., Lindsley, Craig W., Zixiu Xiang, Conn, P. Jeffrey, and Niswender, Colleen M.
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GLUTAMATE receptors ,SYNAPSES ,HIPPOCAMPUS (Brain) ,ALLOSTERIC regulation ,EXCITATORY amino acid agents ,COGNITION disorders treatment - Abstract
Of the eight metabotropic glutamate (mGlu) receptor subtypes, only mGlu
7 is expressed presynaptically at the Schaffer collateral (SC)-CA1 synapse in the hippocampus in adult animals. Coupled with the inhibitory effects of Group III mGlu receptor agonists on transmission at this synapse, mGlu7 is thought to be the predominant autoreceptor responsible for regulating glutamate release at SC terminals. However, the lack of mGlu7 -selective pharmacological tools has hampered direct testing of this hypothesis. We used a novel, selective mGlu7 -negative allosteric modulator (NAM), ADX71743, and a newly described Group III mGlu receptor agonist, LSP4-2022, to elucidate the role of mGlu7 in modulating transmission in hippocampal area CA1 in adult C57BL/6J male mice. Interestingly, although mGlu7 agonists inhibit SC-CA1 EPSPs, we found no evidence for activation of mGlu7 by stimulation of SC-CA1 afferents. However, LSP4-2022 also reduced evoked monosynaptic IPSCs in CA1 pyramidal cells and, in contrast to its effect on SC-CA1 EPSPs, ADX71743 reversed the ability of high-frequency stimulation of SC afferents to reduce IPSC amplitudes. Furthermore, blockade of mGlu7 prevented induction of LTP at the SC-CA1 synapse and activation of mGlu7 potentiated submaximal LTP. Together, these data suggest that mGlu7 serves as a heteroreceptor at inhibitory synapses in area CA1 and that the predominant effect of activation of mGlu7 by stimulation of glutamatergic afferents is disinhibition, rather than reduced excitatory transmission. Furthermore, this mGlu7 -mediated disinhibition is required for induction of LTP at the SC-CA1 synapse, suggesting that mGlu7 could serve as a novel therapeutic target for treatment of cognitive disorders. [ABSTRACT FROM AUTHOR]- Published
- 2015
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5. Discovery and Characterization of a Potent and Selective Inhibitor of Aedes aegypti Inward Rectifier Potassium Channels.
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Raphemot, Rene, Rouhier, Matthew F., Swale, Daniel R., Days, Emily, Weaver, C. David, Lovell, Kimberly M., Konkel, Leah C., Engers, Darren W., Bollinger, Sean F., Hopkins, Corey, Piermarini, Peter M., and Denton, Jerod S.
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AEDES aegypti ,VIRUS disease transmission ,POTASSIUM channels ,DISEASE vectors ,INSECTICIDE resistance ,ELECTROPHYSIOLOGY - Abstract
Vector-borne diseases such as dengue fever and malaria, which are transmitted by infected female mosquitoes, affect nearly half of the world's population. The emergence of insecticide-resistant mosquito populations is reducing the effectiveness of conventional insecticides and threatening current vector control strategies, which has created an urgent need to identify new molecular targets against which novel classes of insecticides can be developed. We previously demonstrated that small molecule inhibitors of mammalian Kir channels represent promising chemicals for new mosquitocide development. In this study, high-throughput screening of approximately 30,000 chemically diverse small-molecules was employed to discover potent and selective inhibitors of Aedes aegypti Kir1 (AeKir1) channels heterologously expressed in HEK293 cells. Of 283 confirmed screening ‘hits’, the small-molecule inhibitor VU625 was selected for lead optimization and in vivo studies based on its potency and selectivity toward AeKir1, and tractability for medicinal chemistry. In patch clamp electrophysiology experiments of HEK293 cells, VU625 inhibits AeKir1 with an IC
50 value of 96.8 nM, making VU625 the most potent inhibitor of AeKir1 described to date. Furthermore, electrophysiology experiments in Xenopus oocytes revealed that VU625 is a weak inhibitor of AeKir2B. Surprisingly, injection of VU625 failed to elicit significant effects on mosquito behavior, urine excretion, or survival. However, when co-injected with probenecid, VU625 inhibited the excretory capacity of mosquitoes and was toxic, suggesting that the compound is a substrate of organic anion and/or ATP-binding cassette (ABC) transporters. The dose-toxicity relationship of VU625 (when co-injected with probenecid) is biphasic, which is consistent with the molecule inhibiting both AeKir1 and AeKir2B with different potencies. This study demonstrates proof-of-concept that potent and highly selective inhibitors of mosquito Kir channels can be developed using conventional drug discovery approaches. Furthermore, it reinforces the notion that the physical and chemical properties that determine a compound's bioavailability in vivo will be critical in determining the efficacy of Kir channel inhibitors as insecticides. [ABSTRACT FROM AUTHOR]- Published
- 2014
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6. An insecticide resistance-breaking mosquitocide targeting inward rectifier potassium channels in vectors of Zika virus and malaria.
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Swale, Daniel R., Engers, Darren W., Bollinger, Sean R., Gross, Aaron, Inocente, Edna Alfaro, Days, Emily, Kanga, Fariba, Johnson, Reed M., Yang, Liu, Bloomquist, Jeffrey R., Hopkins, Corey R., Piermarini, Peter M., and Denton, Jerod S.
- Abstract
Insecticide resistance is a growing threat to mosquito control programs around the world, thus creating the need to discover novel target sites and target-specific compounds for insecticide development. Emerging evidence suggests that mosquito inward rectifier potassium (Kir) channels represent viable molecular targets for developing insecticides with new mechanisms of action. Here we describe the discovery and characterization of VU041, a submicromolar-affinity inhibitor of Anopheles (An.) gambiae and Aedes (Ae.) aegypti Kir1 channels that incapacitates adult female mosquitoes from representative insecticide-susceptible and -resistant strains of An. gambiae (G3 and Akron, respectively) and Ae. aegypti (Liverpool and Puerto Rico, respectively) following topical application. VU041 is selective for mosquito Kir channels over several mammalian orthologs, with the exception of Kir2.1, and is not lethal to honey bees. Medicinal chemistry was used to develop an analog, termed VU730, which retains activity toward mosquito Kir1 but is not active against Kir2.1 or other mammalian Kir channels. Thus, VU041 and VU730 are promising chemical scaffolds for developing new classes of insecticides to combat insecticide-resistant mosquitoes and the transmission of mosquito-borne diseases, such as Zika virus, without harmful effects on humans and beneficial insects. [ABSTRACT FROM AUTHOR]
- Published
- 2016
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7. Identification and Characterization of a Compound That Protects Cardiac Tissue from Human Ether-à-go-go-related Gene (hERG)-related Drug-induced Arrhythmias.
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Potet, Franck, Lorinc, Amanda N., Chaigne, Sebastien, Hopkins, Corey R., Venkataraman, Raghav, Stepanovic, Svetlana Z., Lewis, L. Michelle, Days, Emily, Sidorov, Veniamin Y., Engers, Darren W., Beiyan Zou, Afshartous, David, George Jr., Alfred L., Campbell, Courtney M., Balser, Jeffrey R., Min Li, Baudenbacher, Franz J., Lindsley, Craig W., Weaver, C. David, and Kupershmidt, Sabina
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ARRHYTHMIA , *HEART failure , *HEART diseases , *DOFETILIDE , *PATCH-clamp techniques (Electrophysiology) - Abstract
The human Ether-à-go-go-related gene (hERG)-encoded K+ current, IKr is essential for cardiac repolarization but is also a source of cardiotoxicity because unintendedhERGinhibition by diverse pharmaceuticals can cause arrhythmias and sudden cardiac death. We hypothesized that a small molecule that diminishes IKr block by a known hERG antagonist would constitute a first step toward preventing hERG-related arrhythmias and facilitating drug discovery. Using a high-throughput assay, we screened a library of compounds for agents that increase the IC70 of dofetilide, a well characterized hERG blocker. One compound, VU0405601, with the desired activity was further characterized. In isolated, Langendorff-perfused rabbit hearts, optical mapping revealed that dofetilide-induced arrhythmias were reduced after pretreatment with VU0405601. Patch clamp analysis in stable hERG-HEK cells showed effects on current amplitude, inactivation, and deactivation. VU0405601 increased the IC50 of dofetilide from 38.7 to 76.3 nM. VU0405601 mitigates the effects of hERG blockers from the extracellular aspect primarily by reducing inactivation, whereas most clinically relevant hERG inhibitors act at an inner pore site. Structure-activity relationships surrounding VU0405601 identified a 3-pyridiyl and a naphthyridine ring system as key structural components important for preventing hERG inhibition by multiple inhibitors. These findings indicate that small molecules can be designed to reduce the sensitivity of hERG to inhibitors. [ABSTRACT FROM AUTHOR]
- Published
- 2012
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8. Discovery of "Molecular Switches" within a Series of mGlu 5 Allosteric Ligands Driven by a "Magic Methyl" Effect Affording Both PAMs and NAMs with In Vivo Activity, Derived from an M 1 PAM Chemotype.
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Barbaro L, Rodriguez AL, Blevins AN, Dickerson JW, Billard N, Boutaud O, Rook JL, Niswender CM, Conn PJ, Engers DW, and Lindsley CW
- Abstract
In the course of optimizing an M
1 PAM chemotype, introduction of an ether moiety unexpectedly abolished M1 PAM activity while engendering a "molecular switch" to afford a weak, pure mGlu5 PAM. Further optimization was able to deliver a potent (mGlu5 EC50 = 520 nM, 63% Glu Max), centrally penetrant (Kp = 0.83), MPEP-site binding mGlu5 PAM 17a (VU6036486) that reversed amphetamine-induced hyperlocomotion. A pronounced "magic methyl" effect was noted with a regioisomeric methyl congener, leading to a change in pharmacology to afford a potent (mGlu5 IC50 = 110 nM, 3% Glu Min), centrally penetrant (Kp = 0.94), MPEP-site binding NAM 28d (VU6044766) that displayed anxiolytic activity in a mouse marble burying assay. These data further support the growing body of literature concerning the existence of G protein-coupled receptor (GPCR) allosteric privileged structures, and the value and impact of subtle methyl group walks, as well as the highly productive fluorine walk, around allosteric ligand cores to stabilize unique GPCR conformations., Competing Interests: The authors declare no competing financial interest., (© 2021 The Authors. Published by American Chemical Society.)- Published
- 2021
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9. Discovery of VU6028418: A Highly Selective and Orally Bioavailable M 4 Muscarinic Acetylcholine Receptor Antagonist.
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Spock M, Carter TR, Bollinger KA, Han C, Baker LA, Rodriguez AL, Peng L, Dickerson JW, Qi A, Rook JM, O'Neill JC, Watson KJ, Chang S, Bridges TM, Engers JL, Engers DW, Niswender CM, Conn PJ, Lindsley CW, and Bender AM
- Abstract
Herein, we report the SAR leading to the discovery of VU6028418, a potent M
4 mAChR antagonist with high subtype-selectivity and attractive DMPK properties in vitro and in vivo across multiple species. VU6028418 was subsequently evaluated as a preclinical candidate for the treatment of dystonia and other movement disorders. During the characterization of VU6028418, a novel use of deuterium incorporation as a means to modulate CYP inhibition was also discovered., Competing Interests: The authors declare the following competing financial interest(s): C.M.N., J.W.D., C.W.L., P.J.C., T.M.B., J.M.R., T.R.C., L.A.B., C.H., M.S., J.L.E., D.W.E., and A.M.B. are inventors on applications for composition of matter patents that protect several series of M4 antagonists., (© 2021 American Chemical Society.)- Published
- 2021
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10. Structure-Activity Relationships, Pharmacokinetics, and Pharmacodynamics of the Kir6.2/SUR1-Specific Channel Opener VU0071063.
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Kharade SV, Sanchez-Andres JV, Fulton MG, Shelton EL, Blobaum AL, Engers DW, Hofmann CS, Dadi PK, Lantier L, Jacobson DA, Lindsley CW, and Denton JS
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- Animals, Ductus Arteriosus drug effects, Ductus Arteriosus physiology, Glucose pharmacology, HEK293 Cells, Humans, Insulin Secretion drug effects, Insulin-Secreting Cells cytology, Insulin-Secreting Cells drug effects, Insulin-Secreting Cells metabolism, Mice, Structure-Activity Relationship, Vasodilation drug effects, Xanthines chemistry, Ion Channel Gating drug effects, Potassium Channels, Inwardly Rectifying metabolism, Sulfonylurea Receptors metabolism, Xanthines pharmacokinetics, Xanthines pharmacology
- Abstract
Glucose-stimulated insulin secretion from pancreatic β -cells is controlled by ATP-regulated potassium (K
ATP ) channels composed of Kir6.2 and sulfonylurea receptor 1 (SUR1) subunits. The KATP channel-opener diazoxide is FDA-approved for treating hyperinsulinism and hypoglycemia but suffers from off-target effects on vascular KATP channels and other ion channels. The development of more specific openers would provide critically needed tool compounds for probing the therapeutic potential of Kir6.2/SUR1 activation. Here, we characterize a novel scaffold activator of Kir6.2/SUR1 that our group recently discovered in a high-throughput screen. Optimization efforts with medicinal chemistry identified key structural elements that are essential for VU0071063-dependent opening of Kir6.2/SUR1. VU0071063 has no effects on heterologously expressed Kir6.1/SUR2B channels or ductus arteriole tone, indicating it does not open vascular KATP channels. VU0071063 induces hyperpolarization of β -cell membrane potential and inhibits insulin secretion more potently than diazoxide. VU0071063 exhibits metabolic and pharmacokinetic properties that are favorable for an in vivo probe and is brain penetrant. Administration of VU0071063 inhibits glucose-stimulated insulin secretion and glucose-lowering in mice. Taken together, these studies indicate that VU0071063 is a more potent and specific opener of Kir6.2/SUR1 than diazoxide and should be useful as an in vitro and in vivo tool compound for investigating the therapeutic potential of Kir6.2/SUR1 expressed in the pancreas and brain., (Copyright © 2019 by The American Society for Pharmacology and Experimental Therapeutics.)- Published
- 2019
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11. Discovery of VU2957 (Valiglurax): An mGlu 4 Positive Allosteric Modulator Evaluated as a Preclinical Candidate for the Treatment of Parkinson's Disease.
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Panarese JD, Engers DW, Wu YJ, Bronson JJ, Macor JE, Chun A, Rodriguez AL, Felts AS, Engers JL, Loch MT, Emmitte KA, Castelhano AL, Kates MJ, Nader MA, Jones CK, Blobaum AL, Conn PJ, Niswender CM, Hopkins CR, and Lindsley CW
- Abstract
Herein, we report the discovery of a novel potent, selective, CNS penetrant, and orally bioavailable mGlu
4 PAM, VU0652957 (VU2957, Valiglurax). VU2957 possessed attractive in vitro and in vivo pharmacological and DMPK properties across species. To advance toward the clinic, a spray-dried dispersion (SDD) formulation of VU2957 was developed to support IND-enabling toxicology studies. Based on its overall profile, VU2957 was evaluated as a preclinical development candidate for the treatment of Parkinson's disease., Competing Interests: The authors declare the following competing financial interest(s): Authors hold patents on mGlu4 PAMs and are actively developing mGlu4 PAMs for PD patients.- Published
- 2018
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12. VU6007477, a Novel M 1 PAM Based on a Pyrrolo[2,3- b ]pyridine Carboxamide Core Devoid of Cholinergic Adverse Events.
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Engers JL, Childress ES, Long MF, Capstick RA, Luscombe VB, Cho HP, Dickerson JW, Rook JM, Blobaum AL, Niswender CM, Engers DW, Conn PJ, and Lindsley CW
- Abstract
Herein, we report the chemical optimization of a new series of M
1 positive allosteric modulators (PAMs) based on a novel pyrrolo[2,3- b ]pyridine core, developed via scaffold hopping and iterative parallel synthesis. The vast majority of analogs in this series proved to display robust cholinergic seizure activity. However, by removal of the secondary hydroxyl group, VU6007477 resulted with good rat M1 PAM potency (EC50 = 230 nM, 93% ACh max), minimal M1 agonist activity (agonist EC50 > 10 μM), good CNS penetration (rat brain/plasma Kp = 0.28, Kp,uu = 0.32; mouse Kp = 0.16, Kp,uu = 0.18), and no cholinergic adverse events (AEs, e.g., seizures). This work demonstrates that within a chemical series prone to robust M1 ago-PAM activity, SAR can result, which affords pure M1 PAMs, devoid of cholinergic toxicity/seizure liability., Competing Interests: The authors declare the following competing financial interest(s): Hold IP on M1 PAMs.- Published
- 2018
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13. VU6010608, a Novel mGlu 7 NAM from a Series of N -(2-(1 H -1,2,4-Triazol-1-yl)-5-(trifluoromethoxy)phenyl)benzamides.
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Reed CW, McGowan KM, Spearing PK, Stansley BJ, Roenfanz HF, Engers DW, Rodriguez AL, Engelberg EM, Luscombe VB, Loch MT, Remke DH, Rook JM, Blobaum AL, Conn PJ, Niswender CM, and Lindsley CW
- Abstract
Herein, we report the structure-activity relationships within a series of mGlu
7 NAMs based on an N -(2-(1 H -1,2,4-triazol-1-yl)-5-(trifluoromethoxy)phenyl)benzamide core with excellent CNS penetration ( Kp 1.9-5.8 and Kp,uu 0.4-1.4). Analogues in this series displayed steep SAR. Of these, VU6010608 ( 11a ) emerged with robust efficacy in blocking high frequency stimulated long-term potentiation in electrophysiology studies., Competing Interests: The authors declare no competing financial interest.- Published
- 2017
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14. Discovery of VU6005649, a CNS Penetrant mGlu 7/8 Receptor PAM Derived from a Series of Pyrazolo[1,5- a ]pyrimidines.
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Abe M, Seto M, Gogliotti RG, Loch MT, Bollinger KA, Chang S, Engelberg EM, Luscombe VB, Harp JM, Bubser M, Engers DW, Jones CK, Rodriguez AL, Blobaum AL, Conn PJ, Niswender CM, and Lindsley CW
- Abstract
Herein, we report the structure-activity relationships within a series of mGlu
7 PAMs based on a pyrazolo[1,5- a ]pyrimidine core with excellent CNS penetration ( Kp s > 1 and Kp,uu s > 1). Analogues in this series proved to display a range of Group III mGlu receptor selectivity, but VU6005649 emerged as the first dual mGlu7/8 PAM, filling a void in the Group III mGlu receptor PAM toolbox and demonstrating in vivo efficacy in a mouse contextual fear conditioning model.- Published
- 2017
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15. Discovery of VU0467485/AZ13713945: An M 4 PAM Evaluated as a Preclinical Candidate for the Treatment of Schizophrenia.
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Wood MR, Noetzel MJ, Melancon BJ, Poslusney MS, Nance KD, Hurtado MA, Luscombe VB, Weiner RL, Rodriguez AL, Lamsal A, Chang S, Bubser M, Blobaum AL, Engers DW, Niswender CM, Jones CK, Brandon NJ, Wood MW, Duggan ME, Conn PJ, Bridges TM, and Lindsley CW
- Abstract
Herein, we report the structure-activity relationships within a series of potent, selective, and orally bioavailable muscarinic acetylcholine receptor 4 (M
4 ) positive allosteric modulators (PAMs). Compound 6c (VU0467485) possesses robust in vitro M4 PAM potency across species and in vivo efficacy in preclinical models of schizophrenia. Coupled with an attractive DMPK profile and suitable predicted human PK, 6c (VU0467485) was evaluated as a preclinical development candidate., Competing Interests: The authors declare the following competing financial interest(s): The authors are developing M4 PAMs for the treatment of schizophrenia and hold patents on the same.- Published
- 2016
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16. Activation of Metabotropic Glutamate Receptor 7 Is Required for Induction of Long-Term Potentiation at SC-CA1 Synapses in the Hippocampus.
- Author
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Klar R, Walker AG, Ghose D, Grueter BA, Engers DW, Hopkins CR, Lindsley CW, Xiang Z, Conn PJ, and Niswender CM
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- Animals, CA1 Region, Hippocampal drug effects, CA1 Region, Hippocampal physiology, CA3 Region, Hippocampal cytology, CA3 Region, Hippocampal drug effects, Channelrhodopsins, Electric Stimulation, Excitatory Amino Acid Agonists pharmacology, Excitatory Amino Acid Antagonists pharmacology, In Vitro Techniques, Inhibitory Postsynaptic Potentials drug effects, Inhibitory Postsynaptic Potentials genetics, Male, Mice, Mice, Inbred C57BL, Mice, Transgenic, Models, Biological, Parvalbumins genetics, Patch-Clamp Techniques, CA1 Region, Hippocampal cytology, CA3 Region, Hippocampal physiology, Hippocampus physiology, Interneurons physiology, Long-Term Potentiation physiology, Receptors, Metabotropic Glutamate metabolism
- Abstract
Of the eight metabotropic glutamate (mGlu) receptor subtypes, only mGlu7 is expressed presynaptically at the Schaffer collateral (SC)-CA1 synapse in the hippocampus in adult animals. Coupled with the inhibitory effects of Group III mGlu receptor agonists on transmission at this synapse, mGlu7 is thought to be the predominant autoreceptor responsible for regulating glutamate release at SC terminals. However, the lack of mGlu7-selective pharmacological tools has hampered direct testing of this hypothesis. We used a novel, selective mGlu7-negative allosteric modulator (NAM), ADX71743, and a newly described Group III mGlu receptor agonist, LSP4-2022, to elucidate the role of mGlu7 in modulating transmission in hippocampal area CA1 in adult C57BL/6J male mice. Interestingly, although mGlu7 agonists inhibit SC-CA1 EPSPs, we found no evidence for activation of mGlu7 by stimulation of SC-CA1 afferents. However, LSP4-2022 also reduced evoked monosynaptic IPSCs in CA1 pyramidal cells and, in contrast to its effect on SC-CA1 EPSPs, ADX71743 reversed the ability of high-frequency stimulation of SC afferents to reduce IPSC amplitudes. Furthermore, blockade of mGlu7 prevented induction of LTP at the SC-CA1 synapse and activation of mGlu7 potentiated submaximal LTP. Together, these data suggest that mGlu7 serves as a heteroreceptor at inhibitory synapses in area CA1 and that the predominant effect of activation of mGlu7 by stimulation of glutamatergic afferents is disinhibition, rather than reduced excitatory transmission. Furthermore, this mGlu7-mediated disinhibition is required for induction of LTP at the SC-CA1 synapse, suggesting that mGlu7 could serve as a novel therapeutic target for treatment of cognitive disorders., (Copyright © 2015 the authors 0270-6474/15/357600-16$15.00/0.)
- Published
- 2015
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17. Identification of positive allosteric modulators VU0155094 (ML397) and VU0422288 (ML396) reveals new insights into the biology of metabotropic glutamate receptor 7.
- Author
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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, and Niswender CM
- Subjects
- Acetanilides chemistry, Acetanilides pharmacology, Animals, Benzoates pharmacology, CHO Cells, Calcium metabolism, Cricetulus, Dose-Response Relationship, Drug, Excitatory Postsynaptic Potentials drug effects, G Protein-Coupled Inwardly-Rectifying Potassium Channels genetics, G Protein-Coupled Inwardly-Rectifying Potassium Channels metabolism, Glutamic Acid pharmacology, Glycine analogs & derivatives, Glycine pharmacology, HEK293 Cells, Hippocampus drug effects, Hippocampus metabolism, Humans, In Vitro Techniques, Male, Mice, Inbred C57BL, Picolinic Acids chemistry, Picolinic Acids pharmacology, Propionates pharmacology, Pyrroles chemistry, Pyrroles pharmacology, Rats, Receptors, Metabotropic Glutamate genetics, Structure-Activity Relationship, Thallium metabolism, Transfection, Excitatory Amino Acid Agents chemistry, Excitatory Amino Acid Agents pharmacology, Receptors, Metabotropic Glutamate metabolism
- Abstract
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.
- Published
- 2014
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18. Specific activin receptor-like kinase 3 inhibitors enhance liver regeneration.
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Tsugawa D, Oya Y, Masuzaki R, Ray K, Engers DW, Dib M, Do N, Kuramitsu K, Ho K, Frist A, Yu PB, Bloch KD, Lindsley CW, Hopkins CR, Hong CC, and Karp SJ
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- Animals, Bone Morphogenetic Protein Receptors, Type I metabolism, Humans, Liver Regeneration physiology, Male, Mice, Mice, Inbred C57BL, Protein Kinase Inhibitors chemistry, Bone Morphogenetic Protein Receptors, Type I antagonists & inhibitors, Liver Regeneration drug effects, Protein Kinase Inhibitors pharmacology
- Abstract
Pharmacologic agents to enhance liver regeneration after injury would have wide therapeutic application. Based on previous work suggesting inhibition of bone morphogenetic protein (BMP) signaling stimulates liver regeneration, we tested known and novel BMP inhibitors for their ability to accelerate regeneration in a partial hepatectomy (PH) model. Compounds were produced based on the 3,6-disubstituted pyrazolo[1,5-a] pyrimidine core of the BMP antagonist dorsomorphin and evaluated for their ability to inhibit BMP signaling and enhance liver regeneration. Antagonists of the BMP receptor activin receptor-like kinase 3 (ALK3), including LDN-193189 (LDN; 4-[6-[4-(1-piperazinyl)phenyl]pyrazolo[1,5-a]pyrimidin-3-yl]-quinoline), DMH2 (4-(2-(4-(3-(quinolin-4-yl)pyrazolo[1,5-a]pyrimidin-6-yl)phenoxy)ethyl)morpholine; VU0364849), and the novel compound VU0465350 (7-(4-isopropoxyphenyl)-3-(1H-pyrazol-4-yl)imidazo[1,2-a]pyridine; VU5350), blocked SMAD phosphorylation in vitro and in vivo, and enhanced liver regeneration after PH. In contrast, an antagonist of the BMP receptor ALK2, VU0469381 (5-(6-(4-methoxyphenyl)pyrazolo[1,5-a]pyrimidin-3-yl)quinolone; 1LWY), did not affect liver regeneration. LDN did not affect liver synthetic or metabolic function. Mechanistically, LDN increased serum interleukin-6 levels and signal transducer and activator of transcription 3 phosphorylation in the liver, and modulated other factors known to be important for liver regeneration, including suppressor of cytokine signaling 3 and p53. These findings suggest that inhibition of ALK3 may be part of a therapeutic strategy for treating human liver disease., (Copyright © 2014 by The American Society for Pharmacology and Experimental Therapeutics.)
- Published
- 2014
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19. A novel class of succinimide-derived negative allosteric modulators of metabotropic glutamate receptor subtype 1 provides insight into a disconnect in activity between the rat and human receptors.
- Author
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Cho HP, Engers DW, Venable DF, Niswender CM, Lindsley CW, Conn PJ, Emmitte KA, and Rodriguez AL
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- Amino Acid Sequence, Animals, CHO Cells, Calcium metabolism, Cell Line, Cricetulus, Drug Evaluation, Preclinical, Excitatory Amino Acid Agents chemistry, Fluorescence, HEK293 Cells, High-Throughput Screening Assays, Humans, Mutation, Rats, Receptors, Metabotropic Glutamate genetics, Species Specificity, Succinimides chemistry, Transfection, Excitatory Amino Acid Agents pharmacology, Receptors, Metabotropic Glutamate metabolism, Succinimides pharmacology
- Abstract
Recent progress in the discovery of mGlu₁ allosteric modulators has suggested the modulation of mGlu₁ could offer possible treatment for a number of central nervous system disorders; however, the available chemotypes are inadequate to fully investigate the therapeutic potential of mGlu₁ modulation. To address this issue, we used a fluorescence-based high-throughput screening assay to screen an allosteric modulator-biased library of compounds to generate structurally diverse mGlu₁ negative allosteric modulator hits for chemical optimization. Herein, we describe the discovery and characterization of a novel mGlu₁ chemotype. This series of succinimide negative allosteric modulators, exemplified by VU0410425, exhibited potent inhibitory activity at rat mGlu₁ but was, surprisingly, inactive at human mGlu₁. VU0410425 and a set of chemically diverse mGlu₁ negative allosteric modulators previously reported in the literature were utilized to examine this species disconnect between rat and human mGlu₁ activity. Mutation of the key transmembrane domain residue 757 and functional screening of VU0410425 and the literature compounds suggests that amino acid 757 plays a role in the activity of these compounds, but the contribution of the residue is scaffold specific, ranging from critical to minor. The operational model of allosterism was used to estimate the binding affinities of each compound to compare to functional data. This novel series of mGlu₁ negative allosteric modulators provides valuable insight into the pharmacology underlying the disconnect between rat and human mGlu₁ activity, an issue that must be understood to progress the therapeutic potential of allosteric modulators of mGlu₁.
- Published
- 2014
- Full Text
- View/download PDF
20. Recent progress on the identification of metabotropic glutamate 4 receptor ligands and their potential utility as CNS therapeutics.
- Author
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Robichaud AJ, Engers DW, Lindsley CW, and Hopkins CR
- Subjects
- Allosteric Regulation drug effects, Allosteric Regulation physiology, Animals, Central Nervous System Agents chemistry, Glutamic Acid chemistry, Glutamic Acid metabolism, Glutamic Acid therapeutic use, Humans, Ligands, Neurodegenerative Diseases drug therapy, Neurodegenerative Diseases metabolism, Receptors, Metabotropic Glutamate agonists, Receptors, Metabotropic Glutamate antagonists & inhibitors, Central Nervous System Agents metabolism, Central Nervous System Agents therapeutic use, Drug Discovery trends, Receptors, Metabotropic Glutamate metabolism
- Abstract
This Review describes recent activity in the advancement of ligands for the metabotropic glutamate 4 receptor subtype and their potential utility as central nervous system (CNS) therapeutics. Until recently, there was a paucity of compounds with suitable selectivity and druglike properties to elucidate the value of this target. The search for selective entities has led several groups to the investigation of allosteric modulators as a path to optimization of potential ligands. Recent efforts, discussed here, have afforded a variety of derivatives with improvements in potency, solubility, and pharmacokinetic properties that garner support for continued investigation and optimization.
- Published
- 2011
- Full Text
- View/download PDF
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