The Experts below are selected from a list of 360 Experts worldwide ranked by ideXlab platform
Carrie K Jones - One of the best experts on this subject based on the ideXlab platform.
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discovery structure activity relationship and biological characterization of a novel series of 6 1h pyrazolo 4 3 b pyridin 3 yl amino benzo d isothiazole 3 carboxamides as positive allosteric modulators of the metabotropic glutamate receptor 4 mglu4
Journal of Medicinal Chemistry, 2019Co-Authors: Sean R Bollinger, Carrie K Jones, Darren W Engers, Anna L. Blobaum, Alice L. Rodriguez, Matthew T. Loch, Joseph D Panarese, Mary West, Julie L Engers, Analisa Thompson GrayAbstract:This work describes the discovery and characterization of novel 6-(1H-pyrazolo[4,3-b]pyridin-3-yl)amino-benzo[d]isothiazole-3-carboxamides as mGlu4 PAMs. This scaffold provides improved metabolic clearance and CYP1A2 profiles compared to previously discovered mGlu4 PAMs. From this work, 27o (VU6001376) was identified as a potent (EC50 = 50.1 nM, 50.5% GluMax) and selective mGlu4 PAM with an excellent rat DMPK profile (in vivo rat CLp = 3.1 mL/min/kg, t1/2 = 445 min, CYP1A2 IC50 > 30 μM). Compound 27o was also active in reversing haloperidol induced Catalepsy in a rodent preclinical model of Parkinson’s disease.
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Discovery, Structure–Activity Relationship, and Biological Characterization of a Novel Series of 6‑((1H‑Pyrazolo[4,3‑b]pyridin-3-yl)amino)-benzo[d]isothiazole-3-carboxamides as Positive Allosteric Modulators of the Metabotropic Glutamate Receptor 4 (
2018Co-Authors: Sean R Bollinger, Carrie K Jones, Darren W Engers, Anna L. Blobaum, Alice L. Rodriguez, Matthew T. Loch, Joseph D Panarese, Mary West, Julie L Engers, Analisa Thompson GrayAbstract:This work describes the discovery and characterization of novel 6-(1H-pyrazolo[4,3-b]pyridin-3-yl)amino-benzo[d]isothiazole-3-carboxamides as mGlu4 PAMs. This scaffold provides improved metabolic clearance and CYP1A2 profiles compared to previously discovered mGlu4 PAMs. From this work, 27o (VU6001376) was identified as a potent (EC50 = 50.1 nM, 50.5% GluMax) and selective mGlu4 PAM with an excellent rat DMPK profile (in vivo rat CLp = 3.1 mL/min/kg, t1/2 = 445 min, CYP1A2 IC50 > 30 μM). Compound 27o was also active in reversing haloperidol induced Catalepsy in a rodent preclinical model of Parkinson’s disease
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development and antiparkinsonian activity of vu0418506 a selective positive allosteric modulator of metabotropic glutamate receptor 4 homomers without activity at mglu2 4 heteromers
ACS Chemical Neuroscience, 2016Co-Authors: Colleen M Niswender, Carrie K Jones, Analisa Thompson Gray, Scott J Daniels, Darren W Engers, Michael Bubser, Anna L. Blobaum, Alice L. Rodriguez, Matthew T. Loch, Craig W LindsleyAbstract:Metabotropic glutamate receptor 4 (mGlu4) is emerging as a potential therapeutic target for numerous central nervous system indications, including Parkinson’s disease (PD). As the glutamate binding sites among the eight mGlu receptors are highly conserved, modulation of receptor activity via allosteric sites within the receptor transmembrane domains using positive and negative allosteric modulators (PAMs and NAMs, respectively) has become a common strategy. We and others have used PAMs targeting mGlu4 to show that potentiation of receptor signaling induces antiparkinsonian activity in a variety of PD animal models, including Haloperidol-Induced Catalepsy and 6-hydroxydopamine-induced lesion. Recently, mGlu4 has been reported to form heteromeric complexes with other mGlu receptor subtypes, such as mGlu2, and the resulting heteromer exhibits a distinct pharmacological profile in response to allosteric modulators. For example, some mGlu4 PAMs do not appear to potentiate glutamate activity when mGlu2 and mGlu...
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pharmacological stimulation of metabotropic glutamate receptor type 4 in a rat model of parkinson s disease and l dopa induced dyskinesia comparison between a positive allosteric modulator and an orthosteric agonist
Neuropharmacology, 2015Co-Authors: Hanna Iderberg, Carrie K Jones, Analisa D Thompson, Michael Bubser, Colleen M Niswender, Craig W Lindsley, Natallia Maslava, Corey R Hopkins, Jeffrey P Conn, Angela M CenciAbstract:Metabotropic glutamate receptor 4 (mGlu4) negatively modulates GABA and glutamate release in the 'indirect pathway' of the basal ganglia, and has thus been proposed as a potential target to treat motor symptoms in Parkinson's disease. Here, we present an extensive comparison of the behavioural effects produced by the mGlu4 positive allosteric modulator (PAM), VU0364770, and the mGlu4 orthosteric agonist, LSP1-2111, in rats with unilateral 6-OHDA lesions. The compounds' activity was initially assessed in a test of Haloperidol-Induced Catalepsy in intact rats, and effective doses were then evaluated in the hemiparkinsonian animal model. Neither of the two compounds modified the development of dyskinetic behaviours elicited by chronic treatment with full doses of l-DOPA. When given together with l-DOPA to rats with already established dyskinesias, neither VU0364770 nor LSP1-2111 modified the abnormal involuntary movement scores. VU0364770 potentiated, however, the motor stimulant effect of a subthreshold l-DOPA dose in certain behavioural tests, whereas LSP1-2111 lacked this ability. Taken together, these results indicate that a pharmacological stimulation of mGlu4 lacks intrinsic antidyskinetic activity, but may have DOPA-sparing activity in Parkinson's disease. For the latter indication, mGlu4 PAMs appear to provide a better option than orthosteric agonists.
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the metabotropic glutamate receptor 8 agonist s 3 4 dcpg reverses motor deficits in prolonged but not acute models of parkinson s disease
Neuropharmacology, 2013Co-Authors: Kari A Johnson, Carrie K Jones, Michael Bubser, Jeffrey P Conn, M N Tantawy, Marketa Marvanova, Sib M Ansari, Ronald M Baldwin, Colleen M NiswenderAbstract:Metabotropic glutamate receptors (mGlus) are 7 Transmembrane Spanning Receptors (7TMs) that are differentially expressed throughout the brain and modulate synaptic transmission at both excitatory and inhibitory synapses. Recently, mGlus have been implicated as therapeutic targets for many disorders of the central nervous system, including Parkinson's disease (PD). Previous studies have shown that nonselective agonists of group III mGlus have antiparkinsonian effects in several animal models of PD, suggesting that these receptors represent promising targets for treating the motor symptoms of PD. However, the relative contributions of different group III mGlu subtypes to these effects have not been fully elucidated. Here we report that intracerebroventricular (icv) administration of the mGlu(8)-selective agonist (S)-3,4-dicarboxyphenylglycine (DCPG [ 2.5, 10, or 30 nmol]) does not alleviate motor deficits caused by acute (2 h) treatment with haloperidol or reserpine. However, following prolonged pretreatment with haloperidol (three doses evenly spaced over 18-20 h) or reserpine (18-20 h), DCPG robustly reverses Haloperidol-Induced Catalepsy and reserpine-induced akinesia. Furthermore, DCPG (10 nmol, icv) reverses the long-lasting Catalepsy induced by 20 h pretreatment with the decanoate salt of haloperidol. Finally, icv administration of DCPG ameliorates forelimb use asymmetry caused by unilateral 6-hydroxydopamine lesion of substantia nigra dopamine neurons. These findings suggest that mGlu(8) may partially mediate the antiparkinsonian effects of group III mGlu agonists in animal models of PD in which dopamine depletion or blockade of D(2)-like dopamine receptors is prolonged and indicate that selective activation of mGlu(8) may represent a novel therapeutic strategy for alleviating the motor symptoms of PD. This article is part of a Special Issue entitled 'Metabotropic Glutamate Receptors'.
Anna L. Blobaum - One of the best experts on this subject based on the ideXlab platform.
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discovery structure activity relationship and biological characterization of a novel series of 6 1h pyrazolo 4 3 b pyridin 3 yl amino benzo d isothiazole 3 carboxamides as positive allosteric modulators of the metabotropic glutamate receptor 4 mglu4
Journal of Medicinal Chemistry, 2019Co-Authors: Sean R Bollinger, Carrie K Jones, Darren W Engers, Anna L. Blobaum, Alice L. Rodriguez, Matthew T. Loch, Joseph D Panarese, Mary West, Julie L Engers, Analisa Thompson GrayAbstract:This work describes the discovery and characterization of novel 6-(1H-pyrazolo[4,3-b]pyridin-3-yl)amino-benzo[d]isothiazole-3-carboxamides as mGlu4 PAMs. This scaffold provides improved metabolic clearance and CYP1A2 profiles compared to previously discovered mGlu4 PAMs. From this work, 27o (VU6001376) was identified as a potent (EC50 = 50.1 nM, 50.5% GluMax) and selective mGlu4 PAM with an excellent rat DMPK profile (in vivo rat CLp = 3.1 mL/min/kg, t1/2 = 445 min, CYP1A2 IC50 > 30 μM). Compound 27o was also active in reversing haloperidol induced Catalepsy in a rodent preclinical model of Parkinson’s disease.
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Discovery, Structure–Activity Relationship, and Biological Characterization of a Novel Series of 6‑((1H‑Pyrazolo[4,3‑b]pyridin-3-yl)amino)-benzo[d]isothiazole-3-carboxamides as Positive Allosteric Modulators of the Metabotropic Glutamate Receptor 4 (
2018Co-Authors: Sean R Bollinger, Carrie K Jones, Darren W Engers, Anna L. Blobaum, Alice L. Rodriguez, Matthew T. Loch, Joseph D Panarese, Mary West, Julie L Engers, Analisa Thompson GrayAbstract:This work describes the discovery and characterization of novel 6-(1H-pyrazolo[4,3-b]pyridin-3-yl)amino-benzo[d]isothiazole-3-carboxamides as mGlu4 PAMs. This scaffold provides improved metabolic clearance and CYP1A2 profiles compared to previously discovered mGlu4 PAMs. From this work, 27o (VU6001376) was identified as a potent (EC50 = 50.1 nM, 50.5% GluMax) and selective mGlu4 PAM with an excellent rat DMPK profile (in vivo rat CLp = 3.1 mL/min/kg, t1/2 = 445 min, CYP1A2 IC50 > 30 μM). Compound 27o was also active in reversing haloperidol induced Catalepsy in a rodent preclinical model of Parkinson’s disease
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development and antiparkinsonian activity of vu0418506 a selective positive allosteric modulator of metabotropic glutamate receptor 4 homomers without activity at mglu2 4 heteromers
ACS Chemical Neuroscience, 2016Co-Authors: Colleen M Niswender, Carrie K Jones, Analisa Thompson Gray, Scott J Daniels, Darren W Engers, Michael Bubser, Anna L. Blobaum, Alice L. Rodriguez, Matthew T. Loch, Craig W LindsleyAbstract:Metabotropic glutamate receptor 4 (mGlu4) is emerging as a potential therapeutic target for numerous central nervous system indications, including Parkinson’s disease (PD). As the glutamate binding sites among the eight mGlu receptors are highly conserved, modulation of receptor activity via allosteric sites within the receptor transmembrane domains using positive and negative allosteric modulators (PAMs and NAMs, respectively) has become a common strategy. We and others have used PAMs targeting mGlu4 to show that potentiation of receptor signaling induces antiparkinsonian activity in a variety of PD animal models, including Haloperidol-Induced Catalepsy and 6-hydroxydopamine-induced lesion. Recently, mGlu4 has been reported to form heteromeric complexes with other mGlu receptor subtypes, such as mGlu2, and the resulting heteromer exhibits a distinct pharmacological profile in response to allosteric modulators. For example, some mGlu4 PAMs do not appear to potentiate glutamate activity when mGlu2 and mGlu...
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discovery of 3 aminopicolinamides as metabotropic glutamate receptor subtype 4 mglu4 positive allosteric modulator warheads engendering cns exposure and in vivo efficacy
Bioorganic & Medicinal Chemistry Letters, 2016Co-Authors: Rocco D Gogliotti, Darren W Engers, Anna L. Blobaum, Pedro M Garciabarrantes, Joseph D Panarese, Patrick R Gentry, Ryan D Morrison, Scott J DanielsAbstract:This letter describes the further chemical optimization of the picolinamide-derived family of mGlu4 PAMs wherein we identified a 3-amino substituent to the picolinamide warhead that engendered potency, CNS penetration and in vivo efficacy. From this optimization campaign, VU0477886 emerged as a potent (EC50=95nM, 89% Glu Max) mGlu4 PAM with an attractive DMPK profile (brain:plasma Kp=1.3), rat CLp=4.0mL/min/kg, t1/2=3.7h) and robust efficacy in our standard preclinical Parkinson's disease model, Haloperidol-Induced Catalepsy (HIC).
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the metabotropic glutamate receptor 4 positive allosteric modulator vu0364770 produces efficacy alone and in combination with l dopa or an adenosine 2a antagonist in preclinical rodent models of parkinson s disease
Journal of Pharmacology and Experimental Therapeutics, 2012Co-Authors: Carrie K Jones, Analisa D Thompson, Michael Bubser, Anna L. Blobaum, Ryan D Morrison, Marianne Amalric, Jonathan W Dickerson, Nathalie Turlelorenzo, Thomas M Bridges, Satyawan JadhavAbstract:Parkinson's disease (PD) is a debilitating neurodegenerative disorder associated with severe motor impairments caused by the loss of dopaminergic innervation of the striatum. Previous studies have demonstrated that positive allosteric modulators (PAMs) of metabotropic glutamate receptor 4 (mGlu4), including N-phenyl-7-(hydroxyimino)cyclopropa[b]chromen-1a-carboxamide, can produce antiparkinsonian-like effects in preclinical models of PD. However, these early mGlu4 PAMs exhibited unsuitable physiochemical properties for systemic dosing, requiring intracerebroventricular administration and limiting their broader utility as in vivo tools to further understand the role of mGlu4 in the modulation of basal ganglia function relevant to PD. In the present study, we describe the pharmacologic characterization of a systemically active mGlu4 PAM, N-(3-chlorophenyl)picolinamide (VU0364770), in several rodent PD models. VU0364770 showed efficacy alone or when administered in combination with l-DOPA or an adenosine 2A (A2A) receptor antagonist currently in clinical development (preladenant). When administered alone, VU0364770 exhibited efficacy in reversing Haloperidol-Induced Catalepsy, forelimb asymmetry-induced by unilateral 6-hydroxydopamine (6-OHDA) lesions of the median forebrain bundle, and attentional deficits induced by bilateral 6-OHDA nigrostriatal lesions in rats. In addition, VU0364770 enhanced the efficacy of preladenant to reverse Haloperidol-Induced Catalepsy when given in combination. The effects of VU0364770 to reverse forelimb asymmetry were also potentiated when the compound was coadministered with an inactive dose of l-DOPA, suggesting that mGlu4 PAMs may provide l-DOPA-sparing activity. The present findings provide exciting support for the potential role of selective mGlu4 PAMs as a novel approach for the symptomatic treatment of PD and a possible augmentation strategy with either l-DOPA or A2A antagonists.
Colleen M Niswender - One of the best experts on this subject based on the ideXlab platform.
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development and antiparkinsonian activity of vu0418506 a selective positive allosteric modulator of metabotropic glutamate receptor 4 homomers without activity at mglu2 4 heteromers
ACS Chemical Neuroscience, 2016Co-Authors: Colleen M Niswender, Carrie K Jones, Analisa Thompson Gray, Scott J Daniels, Darren W Engers, Michael Bubser, Anna L. Blobaum, Alice L. Rodriguez, Matthew T. Loch, Craig W LindsleyAbstract:Metabotropic glutamate receptor 4 (mGlu4) is emerging as a potential therapeutic target for numerous central nervous system indications, including Parkinson’s disease (PD). As the glutamate binding sites among the eight mGlu receptors are highly conserved, modulation of receptor activity via allosteric sites within the receptor transmembrane domains using positive and negative allosteric modulators (PAMs and NAMs, respectively) has become a common strategy. We and others have used PAMs targeting mGlu4 to show that potentiation of receptor signaling induces antiparkinsonian activity in a variety of PD animal models, including Haloperidol-Induced Catalepsy and 6-hydroxydopamine-induced lesion. Recently, mGlu4 has been reported to form heteromeric complexes with other mGlu receptor subtypes, such as mGlu2, and the resulting heteromer exhibits a distinct pharmacological profile in response to allosteric modulators. For example, some mGlu4 PAMs do not appear to potentiate glutamate activity when mGlu2 and mGlu...
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pharmacological stimulation of metabotropic glutamate receptor type 4 in a rat model of parkinson s disease and l dopa induced dyskinesia comparison between a positive allosteric modulator and an orthosteric agonist
Neuropharmacology, 2015Co-Authors: Hanna Iderberg, Carrie K Jones, Analisa D Thompson, Michael Bubser, Colleen M Niswender, Craig W Lindsley, Natallia Maslava, Corey R Hopkins, Jeffrey P Conn, Angela M CenciAbstract:Metabotropic glutamate receptor 4 (mGlu4) negatively modulates GABA and glutamate release in the 'indirect pathway' of the basal ganglia, and has thus been proposed as a potential target to treat motor symptoms in Parkinson's disease. Here, we present an extensive comparison of the behavioural effects produced by the mGlu4 positive allosteric modulator (PAM), VU0364770, and the mGlu4 orthosteric agonist, LSP1-2111, in rats with unilateral 6-OHDA lesions. The compounds' activity was initially assessed in a test of Haloperidol-Induced Catalepsy in intact rats, and effective doses were then evaluated in the hemiparkinsonian animal model. Neither of the two compounds modified the development of dyskinetic behaviours elicited by chronic treatment with full doses of l-DOPA. When given together with l-DOPA to rats with already established dyskinesias, neither VU0364770 nor LSP1-2111 modified the abnormal involuntary movement scores. VU0364770 potentiated, however, the motor stimulant effect of a subthreshold l-DOPA dose in certain behavioural tests, whereas LSP1-2111 lacked this ability. Taken together, these results indicate that a pharmacological stimulation of mGlu4 lacks intrinsic antidyskinetic activity, but may have DOPA-sparing activity in Parkinson's disease. For the latter indication, mGlu4 PAMs appear to provide a better option than orthosteric agonists.
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the metabotropic glutamate receptor 8 agonist s 3 4 dcpg reverses motor deficits in prolonged but not acute models of parkinson s disease
Neuropharmacology, 2013Co-Authors: Kari A Johnson, Carrie K Jones, Michael Bubser, Jeffrey P Conn, M N Tantawy, Marketa Marvanova, Sib M Ansari, Ronald M Baldwin, Colleen M NiswenderAbstract:Metabotropic glutamate receptors (mGlus) are 7 Transmembrane Spanning Receptors (7TMs) that are differentially expressed throughout the brain and modulate synaptic transmission at both excitatory and inhibitory synapses. Recently, mGlus have been implicated as therapeutic targets for many disorders of the central nervous system, including Parkinson's disease (PD). Previous studies have shown that nonselective agonists of group III mGlus have antiparkinsonian effects in several animal models of PD, suggesting that these receptors represent promising targets for treating the motor symptoms of PD. However, the relative contributions of different group III mGlu subtypes to these effects have not been fully elucidated. Here we report that intracerebroventricular (icv) administration of the mGlu(8)-selective agonist (S)-3,4-dicarboxyphenylglycine (DCPG [ 2.5, 10, or 30 nmol]) does not alleviate motor deficits caused by acute (2 h) treatment with haloperidol or reserpine. However, following prolonged pretreatment with haloperidol (three doses evenly spaced over 18-20 h) or reserpine (18-20 h), DCPG robustly reverses Haloperidol-Induced Catalepsy and reserpine-induced akinesia. Furthermore, DCPG (10 nmol, icv) reverses the long-lasting Catalepsy induced by 20 h pretreatment with the decanoate salt of haloperidol. Finally, icv administration of DCPG ameliorates forelimb use asymmetry caused by unilateral 6-hydroxydopamine lesion of substantia nigra dopamine neurons. These findings suggest that mGlu(8) may partially mediate the antiparkinsonian effects of group III mGlu agonists in animal models of PD in which dopamine depletion or blockade of D(2)-like dopamine receptors is prolonged and indicate that selective activation of mGlu(8) may represent a novel therapeutic strategy for alleviating the motor symptoms of PD. This article is part of a Special Issue entitled 'Metabotropic Glutamate Receptors'.
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discovery characterization and antiparkinsonian effect of novel positive allosteric modulators of metabotropic glutamate receptor 4
Molecular Pharmacology, 2008Co-Authors: Colleen M Niswender, Zixiu Xiang, Carrie K Jones, Kari A Johnson, Joy E Marlo, Analisa D Thompson, David C Weaver, Alice L. Rodriguez, Tomas De Paulis, Emily DaysAbstract:Parkinson's disease (PD) is caused by the death of dopamine neurons in the basal ganglia and results in motor symptoms such as tremor and bradykinesia. Activation of metabotropic glutamate receptor 4 (mGluR4) has been shown to modulate neurotransmission in the basal ganglia and results in antiparkinsonian effects in rodent PD models. PHCCC is a positive allosteric modulator (PAM) of mGluR4 which has been used to further validate the role of mGluR4 in PD, but the compound suffers from a lack of selectivity, relatively low potency and poor solubility. Via high-throughput screening, we discovered over 400 novel PAMs of mGluR4. Compounds derived from a novel chemical scaffold were characterized in vitro at both rat and human mGluR4 using two distinct assays of mGluR4 function. The lead compound was approximately 8-fold more potent than PHCCC, enhanced the potency of glutamate at mGluR4 by 8-fold, and did not show any significant potentiator or antagonist activity at other mGluR subtypes. Resolution of the regioisomers of the lead revealed that the cis regioisomer, VU0155041, contained the majority of the mGluR4 PAM activity and also exhibited partial agonist activity at mGluR4 at a site that was distinct from the glutamate binding site, suggesting that this compound is a mixed allosteric agonist/PAM of mGluR4. VU0155041 was soluble in an aqueous vehicle and intracerebroventricular administration of 31 to 316 nmol of VU0155041 dose-dependently decreased Haloperidol-Induced Catalepsy and reserpine-induced akinesia in rats. These exciting results provide continued support for mGluR4 as a therapeutic target in PD.
Analisa D Thompson - One of the best experts on this subject based on the ideXlab platform.
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pharmacological stimulation of metabotropic glutamate receptor type 4 in a rat model of parkinson s disease and l dopa induced dyskinesia comparison between a positive allosteric modulator and an orthosteric agonist
Neuropharmacology, 2015Co-Authors: Hanna Iderberg, Carrie K Jones, Analisa D Thompson, Michael Bubser, Colleen M Niswender, Craig W Lindsley, Natallia Maslava, Corey R Hopkins, Jeffrey P Conn, Angela M CenciAbstract:Metabotropic glutamate receptor 4 (mGlu4) negatively modulates GABA and glutamate release in the 'indirect pathway' of the basal ganglia, and has thus been proposed as a potential target to treat motor symptoms in Parkinson's disease. Here, we present an extensive comparison of the behavioural effects produced by the mGlu4 positive allosteric modulator (PAM), VU0364770, and the mGlu4 orthosteric agonist, LSP1-2111, in rats with unilateral 6-OHDA lesions. The compounds' activity was initially assessed in a test of Haloperidol-Induced Catalepsy in intact rats, and effective doses were then evaluated in the hemiparkinsonian animal model. Neither of the two compounds modified the development of dyskinetic behaviours elicited by chronic treatment with full doses of l-DOPA. When given together with l-DOPA to rats with already established dyskinesias, neither VU0364770 nor LSP1-2111 modified the abnormal involuntary movement scores. VU0364770 potentiated, however, the motor stimulant effect of a subthreshold l-DOPA dose in certain behavioural tests, whereas LSP1-2111 lacked this ability. Taken together, these results indicate that a pharmacological stimulation of mGlu4 lacks intrinsic antidyskinetic activity, but may have DOPA-sparing activity in Parkinson's disease. For the latter indication, mGlu4 PAMs appear to provide a better option than orthosteric agonists.
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roles of the m1 muscarinic acetylcholine receptor subtype in the regulation of basal ganglia function and implications for the treatment of parkinson s disease
Journal of Pharmacology and Experimental Therapeutics, 2012Co-Authors: Zixiu Xiang, Carrie K Jones, Analisa D Thompson, Craig W Lindsley, Jeffrey P ConnAbstract:Antagonists of the muscarinic acetylcholine receptors (mAChRs) were among the first treatments for Parkinson9s disease. However, the clinical utility of mAChR antagonists is limited by adverse effects associated with the blockade of multiple mAChR subtypes. Understanding the roles of specific mAChR subtypes in regulating basal ganglia and motor function could lead to the development of novel agents that have antiparkinsonian activity with fewer adverse effects. Using the novel, highly selective M1 antagonist N -[3-oxo-3-[4-(4-pyridinyl)-1-piperazinyl]propyl]-2,1,3-benzothiadiazole-4-sulfonamide (VU0255035) and the M1 positive allosteric modulator benzylquinolone carboxylic acid, we investigated the roles of M1 receptors in cholinergic excitation and regulation of synaptic transmission in striatal medium spiny neurons (MSNs) and neurons in the subthalamic nucleus (STN) and substantia nigra pars reticulata (SNr). Electrophysiological studies demonstrate that M1 activation has excitatory effects on MSNs but plays little or no role in mAChR-mediated increases in firing frequency or the regulation of synaptic transmission in STN and SNr neurons. On the basis of this profile, M1-selective antagonists may have weak antiparkinsonian activity but would not have the full efficacy observed in nonselective mAChR antagonists. Consistent with this, the M1-selective antagonist VU0255035 partially reversed reserpine-induced akinesia and decreased Haloperidol-Induced Catalepsy in rats but did not have the full efficacy observed with the nonselective mAChR antagonist scopolamine. These results suggest that the M1 receptor participates in the overall regulation of basal ganglia function and antiparkinsonian effects of mAChR antagonists but that other mAChR subtype(s) also play important roles at multiple levels of the basal ganglia motor circuit.
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the metabotropic glutamate receptor 4 positive allosteric modulator vu0364770 produces efficacy alone and in combination with l dopa or an adenosine 2a antagonist in preclinical rodent models of parkinson s disease
Journal of Pharmacology and Experimental Therapeutics, 2012Co-Authors: Carrie K Jones, Analisa D Thompson, Michael Bubser, Anna L. Blobaum, Ryan D Morrison, Marianne Amalric, Jonathan W Dickerson, Nathalie Turlelorenzo, Thomas M Bridges, Satyawan JadhavAbstract:Parkinson's disease (PD) is a debilitating neurodegenerative disorder associated with severe motor impairments caused by the loss of dopaminergic innervation of the striatum. Previous studies have demonstrated that positive allosteric modulators (PAMs) of metabotropic glutamate receptor 4 (mGlu4), including N-phenyl-7-(hydroxyimino)cyclopropa[b]chromen-1a-carboxamide, can produce antiparkinsonian-like effects in preclinical models of PD. However, these early mGlu4 PAMs exhibited unsuitable physiochemical properties for systemic dosing, requiring intracerebroventricular administration and limiting their broader utility as in vivo tools to further understand the role of mGlu4 in the modulation of basal ganglia function relevant to PD. In the present study, we describe the pharmacologic characterization of a systemically active mGlu4 PAM, N-(3-chlorophenyl)picolinamide (VU0364770), in several rodent PD models. VU0364770 showed efficacy alone or when administered in combination with l-DOPA or an adenosine 2A (A2A) receptor antagonist currently in clinical development (preladenant). When administered alone, VU0364770 exhibited efficacy in reversing Haloperidol-Induced Catalepsy, forelimb asymmetry-induced by unilateral 6-hydroxydopamine (6-OHDA) lesions of the median forebrain bundle, and attentional deficits induced by bilateral 6-OHDA nigrostriatal lesions in rats. In addition, VU0364770 enhanced the efficacy of preladenant to reverse Haloperidol-Induced Catalepsy when given in combination. The effects of VU0364770 to reverse forelimb asymmetry were also potentiated when the compound was coadministered with an inactive dose of l-DOPA, suggesting that mGlu4 PAMs may provide l-DOPA-sparing activity. The present findings provide exciting support for the potential role of selective mGlu4 PAMs as a novel approach for the symptomatic treatment of PD and a possible augmentation strategy with either l-DOPA or A2A antagonists.
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discovery synthesis and structure activity relationship development of a series of n 4 2 5 dioxopyrrolidin 1 yl phenylpicolinamides vu0400195 ml182 characterization of a novel positive allosteric modulator of the metabotropic glutamate receptor 4 mgl
Journal of Medicinal Chemistry, 2011Co-Authors: Carrie K Jones, Analisa D Thompson, Darren W Engers, Anna L. Blobaum, Rocco D Gogliotti, Satyawan Jadhav, Julie R Field, Stacey R Lindsley, Ya Zhou, Rocio ZamoranoAbstract:There is an increasing amount of literature data showing the positive effects on preclinical antiparkinsonian rodent models with selective positive allosteric modulators of metabotropic glutamate receptor 4 (mGlu4). However, most of the data generated utilize compounds that have not been optimized for druglike properties, and as a consequence, they exhibit poor pharmacokinetic properties and thus do not cross the blood–brain barrier. Herein, we report on a series of N-4-(2,5-dioxopyrrolidin-1-yl)phenylpicolinamides with improved PK properties with excellent potency and selectivity as well as improved brain exposure in rodents. Finally, ML182 was shown to be orally active in the haloperidol induced Catalepsy model, a well-established antiparkinsonian model.
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discovery characterization and antiparkinsonian effect of novel positive allosteric modulators of metabotropic glutamate receptor 4
Molecular Pharmacology, 2008Co-Authors: Colleen M Niswender, Zixiu Xiang, Carrie K Jones, Kari A Johnson, Joy E Marlo, Analisa D Thompson, David C Weaver, Alice L. Rodriguez, Tomas De Paulis, Emily DaysAbstract:Parkinson's disease (PD) is caused by the death of dopamine neurons in the basal ganglia and results in motor symptoms such as tremor and bradykinesia. Activation of metabotropic glutamate receptor 4 (mGluR4) has been shown to modulate neurotransmission in the basal ganglia and results in antiparkinsonian effects in rodent PD models. PHCCC is a positive allosteric modulator (PAM) of mGluR4 which has been used to further validate the role of mGluR4 in PD, but the compound suffers from a lack of selectivity, relatively low potency and poor solubility. Via high-throughput screening, we discovered over 400 novel PAMs of mGluR4. Compounds derived from a novel chemical scaffold were characterized in vitro at both rat and human mGluR4 using two distinct assays of mGluR4 function. The lead compound was approximately 8-fold more potent than PHCCC, enhanced the potency of glutamate at mGluR4 by 8-fold, and did not show any significant potentiator or antagonist activity at other mGluR subtypes. Resolution of the regioisomers of the lead revealed that the cis regioisomer, VU0155041, contained the majority of the mGluR4 PAM activity and also exhibited partial agonist activity at mGluR4 at a site that was distinct from the glutamate binding site, suggesting that this compound is a mixed allosteric agonist/PAM of mGluR4. VU0155041 was soluble in an aqueous vehicle and intracerebroventricular administration of 31 to 316 nmol of VU0155041 dose-dependently decreased Haloperidol-Induced Catalepsy and reserpine-induced akinesia in rats. These exciting results provide continued support for mGluR4 as a therapeutic target in PD.
Darren W Engers - One of the best experts on this subject based on the ideXlab platform.
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discovery structure activity relationship and biological characterization of a novel series of 6 1h pyrazolo 4 3 b pyridin 3 yl amino benzo d isothiazole 3 carboxamides as positive allosteric modulators of the metabotropic glutamate receptor 4 mglu4
Journal of Medicinal Chemistry, 2019Co-Authors: Sean R Bollinger, Carrie K Jones, Darren W Engers, Anna L. Blobaum, Alice L. Rodriguez, Matthew T. Loch, Joseph D Panarese, Mary West, Julie L Engers, Analisa Thompson GrayAbstract:This work describes the discovery and characterization of novel 6-(1H-pyrazolo[4,3-b]pyridin-3-yl)amino-benzo[d]isothiazole-3-carboxamides as mGlu4 PAMs. This scaffold provides improved metabolic clearance and CYP1A2 profiles compared to previously discovered mGlu4 PAMs. From this work, 27o (VU6001376) was identified as a potent (EC50 = 50.1 nM, 50.5% GluMax) and selective mGlu4 PAM with an excellent rat DMPK profile (in vivo rat CLp = 3.1 mL/min/kg, t1/2 = 445 min, CYP1A2 IC50 > 30 μM). Compound 27o was also active in reversing haloperidol induced Catalepsy in a rodent preclinical model of Parkinson’s disease.
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Discovery, Structure–Activity Relationship, and Biological Characterization of a Novel Series of 6‑((1H‑Pyrazolo[4,3‑b]pyridin-3-yl)amino)-benzo[d]isothiazole-3-carboxamides as Positive Allosteric Modulators of the Metabotropic Glutamate Receptor 4 (
2018Co-Authors: Sean R Bollinger, Carrie K Jones, Darren W Engers, Anna L. Blobaum, Alice L. Rodriguez, Matthew T. Loch, Joseph D Panarese, Mary West, Julie L Engers, Analisa Thompson GrayAbstract:This work describes the discovery and characterization of novel 6-(1H-pyrazolo[4,3-b]pyridin-3-yl)amino-benzo[d]isothiazole-3-carboxamides as mGlu4 PAMs. This scaffold provides improved metabolic clearance and CYP1A2 profiles compared to previously discovered mGlu4 PAMs. From this work, 27o (VU6001376) was identified as a potent (EC50 = 50.1 nM, 50.5% GluMax) and selective mGlu4 PAM with an excellent rat DMPK profile (in vivo rat CLp = 3.1 mL/min/kg, t1/2 = 445 min, CYP1A2 IC50 > 30 μM). Compound 27o was also active in reversing haloperidol induced Catalepsy in a rodent preclinical model of Parkinson’s disease
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development and antiparkinsonian activity of vu0418506 a selective positive allosteric modulator of metabotropic glutamate receptor 4 homomers without activity at mglu2 4 heteromers
ACS Chemical Neuroscience, 2016Co-Authors: Colleen M Niswender, Carrie K Jones, Analisa Thompson Gray, Scott J Daniels, Darren W Engers, Michael Bubser, Anna L. Blobaum, Alice L. Rodriguez, Matthew T. Loch, Craig W LindsleyAbstract:Metabotropic glutamate receptor 4 (mGlu4) is emerging as a potential therapeutic target for numerous central nervous system indications, including Parkinson’s disease (PD). As the glutamate binding sites among the eight mGlu receptors are highly conserved, modulation of receptor activity via allosteric sites within the receptor transmembrane domains using positive and negative allosteric modulators (PAMs and NAMs, respectively) has become a common strategy. We and others have used PAMs targeting mGlu4 to show that potentiation of receptor signaling induces antiparkinsonian activity in a variety of PD animal models, including Haloperidol-Induced Catalepsy and 6-hydroxydopamine-induced lesion. Recently, mGlu4 has been reported to form heteromeric complexes with other mGlu receptor subtypes, such as mGlu2, and the resulting heteromer exhibits a distinct pharmacological profile in response to allosteric modulators. For example, some mGlu4 PAMs do not appear to potentiate glutamate activity when mGlu2 and mGlu...
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discovery of 3 aminopicolinamides as metabotropic glutamate receptor subtype 4 mglu4 positive allosteric modulator warheads engendering cns exposure and in vivo efficacy
Bioorganic & Medicinal Chemistry Letters, 2016Co-Authors: Rocco D Gogliotti, Darren W Engers, Anna L. Blobaum, Pedro M Garciabarrantes, Joseph D Panarese, Patrick R Gentry, Ryan D Morrison, Scott J DanielsAbstract:This letter describes the further chemical optimization of the picolinamide-derived family of mGlu4 PAMs wherein we identified a 3-amino substituent to the picolinamide warhead that engendered potency, CNS penetration and in vivo efficacy. From this optimization campaign, VU0477886 emerged as a potent (EC50=95nM, 89% Glu Max) mGlu4 PAM with an attractive DMPK profile (brain:plasma Kp=1.3), rat CLp=4.0mL/min/kg, t1/2=3.7h) and robust efficacy in our standard preclinical Parkinson's disease model, Haloperidol-Induced Catalepsy (HIC).
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discovery synthesis and structure activity relationship development of a series of n 4 2 5 dioxopyrrolidin 1 yl phenylpicolinamides vu0400195 ml182 characterization of a novel positive allosteric modulator of the metabotropic glutamate receptor 4 mgl
Journal of Medicinal Chemistry, 2011Co-Authors: Carrie K Jones, Analisa D Thompson, Darren W Engers, Anna L. Blobaum, Rocco D Gogliotti, Satyawan Jadhav, Julie R Field, Stacey R Lindsley, Ya Zhou, Rocio ZamoranoAbstract:There is an increasing amount of literature data showing the positive effects on preclinical antiparkinsonian rodent models with selective positive allosteric modulators of metabotropic glutamate receptor 4 (mGlu4). However, most of the data generated utilize compounds that have not been optimized for druglike properties, and as a consequence, they exhibit poor pharmacokinetic properties and thus do not cross the blood–brain barrier. Herein, we report on a series of N-4-(2,5-dioxopyrrolidin-1-yl)phenylpicolinamides with improved PK properties with excellent potency and selectivity as well as improved brain exposure in rodents. Finally, ML182 was shown to be orally active in the haloperidol induced Catalepsy model, a well-established antiparkinsonian model.
