36 results on '"Colleen M. Niswender"'
Search Results
2. Discovery of VU6028418: A Highly Selective and Orally Bioavailable M4 Muscarinic Acetylcholine Receptor Antagonist
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Sichen Chang, Jonathan W. Dickerson, Baker Logan A, Thomas M. Bridges, Craig W. Lindsley, Darren W. Engers, Aidong Qi, Jerri M. Rook, Aaron M. Bender, P. Jeffrey Conn, Katrina A. Bollinger, Colleen M. Niswender, Changho Han, Alice L. Rodriguez, Trever R Carter, Li Peng, Julie L. Engers, Jordan C. O’Neill, Matthew Spock, and Katherine J. Watson
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Dystonia ,Movement disorders ,Chemistry ,Organic Chemistry ,Antagonist ,Pharmacology ,medicine.disease ,Highly selective ,Biochemistry ,In vitro ,Bioavailability ,In vivo ,Drug Discovery ,Muscarinic acetylcholine receptor ,medicine ,medicine.symptom - Abstract
[Image: see text] 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.
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- 2021
3. Discovery of the First Selective M4 Muscarinic Acetylcholine Receptor Antagonists with in Vivo Antiparkinsonian and Antidystonic Efficacy
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Jerri M. Rook, Aaron M. Bender, Colleen M. Niswender, Yuping Donsante, P. Jeffrey Conn, Hyekyung P. Cho, Li Peng, Julie L. Engers, Jonathan W. Dickerson, Thomas M. Bridges, Craig W. Lindsley, Ellen J. Hess, Sichen Chang, Aidong Qi, Weimin Peng, Mark S. Moehle, Jordan C. O’Neill, Daniel J. Foster, Alice L. Rodriguez, Zoey Bryant, Katherine J. Watson, and Kaylee J. Stillwell
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Pharmacology ,Dystonia ,Movement disorders ,business.industry ,Central nervous system ,medicine.disease ,chemistry.chemical_compound ,medicine.anatomical_structure ,chemistry ,Tolerability ,In vivo ,Muscarinic acetylcholine receptor ,Genetic model ,Medicine ,Pharmacology (medical) ,medicine.symptom ,business ,Neurotransmitter - Abstract
Nonselective antagonists of muscarinic acetylcholine receptors (mAChRs) that broadly inhibit all five mAChR subtypes provide an efficacious treatment for some movement disorders, including Parkinson's disease and dystonia. Despite their efficacy in these and other central nervous system disorders, antimuscarinic therapy has limited utility due to severe adverse effects that often limit their tolerability by patients. Recent advances in understanding the roles that each mAChR subtype plays in disease pathology suggest that highly selective ligands for individual subtypes may underlie the antiparkinsonian and antidystonic efficacy observed with the use of nonselective antimuscarinic therapeutics. Our recent work has indicated that the M4 muscarinic acetylcholine receptor has several important roles in opposing aberrant neurotransmitter release, intracellular signaling pathways, and brain circuits associated with movement disorders. This raises the possibility that selective antagonists of M4 may recapitulate the efficacy of nonselective antimuscarinic therapeutics and may decrease or eliminate the adverse effects associated with these drugs. However, this has not been directly tested due to lack of selective antagonists of M4. Here, we utilize genetic mAChR knockout animals in combination with nonselective mAChR antagonists to confirm that the M4 receptor activation is required for the locomotor-stimulating and antiparkinsonian efficacy in rodent models. We also report the synthesis, discovery, and characterization of the first-in-class selective M4 antagonists VU6013720, VU6021302, and VU6021625 and confirm that these optimized compounds have antiparkinsonian and antidystonic efficacy in pharmacological and genetic models of movement disorders.
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- 2021
4. Discovery of VU6027459: A First-in-Class Selective and CNS Penetrant mGlu7 Positive Allosteric Modulator Tool Compound
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Carson W. Reed, Jordan P Washecheck, Alice L. Rodriguez, P. Jeffrey Conn, Anna L. Blobaum, Colleen M. Niswender, Ashton Hunter, Craig W. Lindsley, Madison J Wong, and Jacob J. Kalbfleisch
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Allosteric modulator ,010405 organic chemistry ,Organic Chemistry ,Rett syndrome ,Pharmacology ,medicine.disease ,01 natural sciences ,Biochemistry ,0104 chemical sciences ,Cns penetration ,010404 medicinal & biomolecular chemistry ,chemistry.chemical_compound ,chemistry ,Metabotropic glutamate receptor ,Drug Discovery ,medicine ,Penetrant (biochemical) - Abstract
Herein, we report the discovery of the first selective and CNS penetrant mGlu7 PAM (VU6027459) derived from a "molecular switch" within a selective mGlu7 NAM chemotype. VU6027459 displayed CNS penetration in both mice (Kp = 2.74) and rats (Kp= 4.78), it was orally bioavailable in rats (%F = 69.5), and undesired activity at DAT was ablated.
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- 2020
5. In Vitro to in Vivo Translation of Allosteric Modulator Concentration-Effect Relationships: Implications for Drug Discovery
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Shaun R. Stauffer, Rocco G. Gogliotti, P. Jeffrey Conn, Craig W. Lindsley, Carrie K. Jones, Thomas M. Bridges, Colleen M. Niswender, Karen J. Gregory, and Meredith J. Noetzel
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Pharmacology ,Allosteric modulator ,Drug discovery ,Metabotropic glutamate receptor 5 ,Chemistry ,Allosteric regulation ,Cooperativity ,Mechanism of action ,Drug development ,In vivo ,parasitic diseases ,medicine ,Biophysics ,Pharmacology (medical) ,medicine.symptom - Abstract
[Image: see text] Allosteric modulation of GPCRs represents an increasingly explored approach in drug development. Due to complex pharmacology, however, the relationship(s) between modulator properties determined in vitro with in vivo concentration-effect phenomena is frequently unclear. We investigated key pharmacological properties of a set of metabotropic glutamate receptor 5 (mGlu(5)) positive allosteric modulators (PAMs) and their relevance to in vivo concentration–response relationships. These studies identified a significant relationship between in vitro PAM cooperativity (αβ), as well as the maximal response obtained from a simple in vitro PAM concentration–response experiment, with in vivo efficacy for reversal of amphetamine-induced hyperlocomotion. This correlation did not exist with PAM potency or affinity. Data across PAMs were then converged to calculate an in vivo concentration of glutamate putatively relevant to the mGlu(5) PAM mechanism of action. This work demonstrates the ability to merge in vitro pharmacology profiles with relevant behavioral outcomes and also provides a novel method to estimate neurotransmitter concentrations in vivo.
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- 2019
6. Evaluation of Synthetic Cytochrome P450-Mimetic Metalloporphyrins To Facilitate 'Biomimetic' Biotransformation of a Series of mGlu5 Allosteric Ligands
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Colleen M. Niswender, Christopher C Presley, P. Jeffrey Conn, Vincent B. Luscombe, Alice L. Rodriguez, Charles K. Perry, Craig W. Lindsley, Matthew J. Mulder, and Elizabeth S. Childress
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Molecular switch ,Cytochrome ,biology ,Ligand ,General Chemical Engineering ,Metabolite ,Allosteric regulation ,General Chemistry ,Combinatorial chemistry ,lcsh:Chemistry ,chemistry.chemical_compound ,lcsh:QD1-999 ,chemistry ,Biotransformation ,In vivo ,biology.protein ,G protein-coupled receptor - Abstract
Allosteric ligands within a given chemotype can have the propensity to display a wide range of pharmacology, as well as unexpected changes in GPCR subtype selectivity, typically mediated by single-atom modifications to the ligand. Due to the unexpected nature of these "molecular switches", chemotypes with this property are typically abandoned in lead optimization. Recently, we have found that in vivo oxidative metabolism by CYP450s can also engender molecular switches within allosteric ligands, changing the mode of pharmacology and leading to unwanted toxicity. We required a higher-throughput approach to assess in vivo metabolic molecular switches, and we turned to a "synthetic liver", a 96 well kit of biomimetic catalysts (e.g., metalloporphyrins) to rapidly survey a broad panel of synthetic CYP450s' ability to oxidize/"metabolize" an mGlu5 PAM (VU0403602) known to undergo an in vivo CYP450-mediated molecular switch. While the synthetic CYP450s did generate a number of oxidative "metabolites" at known "hot spots", several of which proved to be pure mGlu5 PAMs comparable in potency to the parent, the known CYP450-mediated in vivo ago-PAM metabolite, namely, VU0453103, was not formed. Thus, this technology platform has potential to identify hot spots for oxidative metabolism and produce active metabolites of small-molecule ligands in a high-throughput, scalable manner.
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- 2019
7. mGlu5 Positive Allosteric Modulators Facilitate Long-Term Potentiation via Disinhibition Mediated by mGlu5-Endocannabinoid Signaling
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Colleen M. Niswender, P. Jeffrey Conn, Branden J. Stansley, Ayan Ghoshal, Rocco G. Gogliotti, Zixiu Xiang, Craig W. Lindsley, Xiaohui Lv, and James Maksymetz
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Pharmacology ,AM251 ,0303 health sciences ,Chemistry ,musculoskeletal, neural, and ocular physiology ,Long-term potentiation ,Inhibitory postsynaptic potential ,Endocannabinoid system ,03 medical and health sciences ,0302 clinical medicine ,medicine.anatomical_structure ,Metabotropic receptor ,nervous system ,Schaffer collateral ,Cannabinoid receptor type 1 ,medicine ,NMDA receptor ,Pharmacology (medical) ,Neuroscience ,psychological phenomena and processes ,030217 neurology & neurosurgery ,030304 developmental biology ,medicine.drug - Abstract
[Image: see text] Metabotropic glutamate (mGlu) receptor type 5 (mGlu(5)) positive allosteric modulators (PAMs) enhance hippocampal long-term potentiation (LTP) and have cognition-enhancing effects in animal models. These effects were initially thought to be mediated by potentiation of mGlu(5) modulation of N-methyl-d-aspartate receptor (NMDAR) currents. However, a biased mGlu(5) PAM that potentiates Gα(q)-dependent mGlu(5) signaling, but not mGlu(5) modulation of NMDAR currents, retains cognition-enhancing effects in animal models, suggesting that potentiation of NMDAR currents is not required for these in vivo effects of mGlu(5) PAMs. However, it is not clear whether the potentiation of NMDAR currents is critical for the ability of mGlu(5) PAMs to enhance hippocampal LTP. We now report the characterization of effects of two structurally distinct mGlu(5) PAMs, VU-29 and VU0092273, on NMDAR currents and hippocampal LTP. As with other mGlu(5) PAMs that do not display observable bias for potentiation of NMDAR currents, VU0092273 enhanced both mGlu(5) modulation of NMDAR currents and induction of LTP at the hippocampal Schaffer collateral (SC)-CA1 synapse. In contrast, VU-29 did not potentiate mGlu(5) modulation of NMDAR currents but induced robust potentiation of hippocampal LTP. Interestingly, both VU-29 and VU0092273 suppressed evoked inhibitory postsynaptic currents (eIPSCs) in CA1 pyramidal cells, and this effect was blocked by the cannabinoid receptor type 1 (CB1) antagonist AM251. Furthermore, AM251 blocked the ability of both mGlu(5) PAMs to enhance LTP. Finally, both PAMs failed to enhance LTP in mice with the restricted genetic deletion of mGlu(5) in CA1 pyramidal cells. Taken together with previous findings, these results suggest that enhancement of LTP by mGlu(5) PAMs does not depend on mGlu(5) modulation of NMDAR currents but is mediated by a previously established mechanism in which mGlu(5) in CA1 pyramidal cells induces endocannabinoid release and CB1-dependent disinhibition.
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- 2019
8. Discovery of Novel Central Nervous System Penetrant Metabotropic Glutamate Receptor Subtype 2 (mGlu2) Negative Allosteric Modulators (NAMs) Based on Functionalized Pyrazolo[1,5-a]pyrimidine-5-carboxamide and Thieno[3,2-b]pyridine-5-carboxamide Cores
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Colleen M. Niswender, Craig W. Lindsley, Andrew S. Felts, Vincent B. Luscombe, P. Jeffrey Conn, Hyekyung P. Cho, Elizabeth S. Childress, Megan M. Breiner, Joshua M. Wieting, Kyle A. Emmitte, Madeline F. Long, Alice L. Rodriguez, and Anna L. Blobaum
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0303 health sciences ,Pyrimidine ,medicine.drug_class ,Stereochemistry ,Allosteric regulation ,Carboxamide ,01 natural sciences ,0104 chemical sciences ,010404 medicinal & biomolecular chemistry ,03 medical and health sciences ,chemistry.chemical_compound ,chemistry ,Metabotropic glutamate receptor ,Drug Discovery ,Pyridine ,medicine ,Molecular Medicine ,Structure–activity relationship ,Selectivity ,Receptor ,030304 developmental biology - Abstract
A scaffold hopping exercise from a monocyclic mGlu2 NAM with poor rodent PK led to two novel heterobicyclic series of mGlu2 NAMs based on either a functionalized pyrazolo[1,5- a]pyrimidine-5-carboxamide core or a thieno[3,2- b]pyridine-5-carboxamide core. These novel analogues possess enhanced rodent PK, while also maintaining good mGlu2 NAM potency, selectivity (versus mGlu3 and the remaining six mGlu receptors), and high CNS penetration. Interestingly, SAR was divergent between the new 5,6-heterobicyclic systems.
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- 2018
9. Discovery of VU2957 (Valiglurax): An mGlu4 Positive Allosteric Modulator Evaluated as a Preclinical Candidate for the Treatment of Parkinson’s Disease
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Michael J. Kates, Arlindo L. Castelhano, Carrie K. Jones, Colleen M. Niswender, Andrew S. Felts, Anna L. Blobaum, Matthew T. Loch, Kyle A. Emmitte, Aspen Chun, John E. Macor, Joanne J. Bronson, Darren W. Engers, Alice L. Rodriguez, Julie L. Engers, Joseph D. Panarese, Craig W. Lindsley, Michael A. Nader, Wu Yong Jin, P. Jeffrey Conn, and Corey R. Hopkins
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Allosteric modulator ,Parkinson's disease ,010405 organic chemistry ,business.industry ,Organic Chemistry ,Pharmacology ,medicine.disease ,01 natural sciences ,Biochemistry ,0104 chemical sciences ,Toxicology studies ,010404 medicinal & biomolecular chemistry ,chemistry.chemical_compound ,chemistry ,In vivo ,Drug Discovery ,medicine ,business ,Penetrant (biochemical) - Abstract
[Image: see text] 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.
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- 2018
10. 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)
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Julie L. Engers, Alice L. Rodriguez, Analisa D. Thompson Gray, Corey R. Hopkins, Darren W. Engers, Anna L. Blobaum, Sean R. Bollinger, P. Jeffrey Conn, Colleen M. Niswender, Mary West, Carrie K. Jones, Joseph D. Panarese, Craig W. Lindsley, and Matthew T. Loch
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Male ,Stereochemistry ,Allosteric regulation ,Receptors, Metabotropic Glutamate ,01 natural sciences ,Rats, Sprague-Dawley ,Structure-Activity Relationship ,03 medical and health sciences ,chemistry.chemical_compound ,Allosteric Regulation ,Cytochrome P-450 CYP1A2 ,In vivo ,Drug Discovery ,Animals ,Humans ,Structure–activity relationship ,Receptor ,IC50 ,030304 developmental biology ,Catalepsy ,0303 health sciences ,Isothiazole ,Metabotropic glutamate receptor 4 ,CYP1A2 ,Brain ,Isoxazoles ,Amides ,Rats ,0104 chemical sciences ,010404 medicinal & biomolecular chemistry ,chemistry ,Haloperidol ,Molecular Medicine ,Half-Life - Abstract
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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- 2018
11. VU6007477, a Novel M1 PAM Based on a Pyrrolo[2,3-b]pyridine Carboxamide Core Devoid of Cholinergic Adverse Events
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Anna L. Blobaum, Jerri M. Rook, Jonathan W. Dickerson, Colleen M. Niswender, Julie L. Engers, Hekyung P Cho, Elizabeth S. Childress, Darren W. Engers, Rory A. Capstick, P. Jeffrey Conn, Craig W. Lindsley, Vincent B. Luscombe, and Madeline F. Long
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0301 basic medicine ,Agonist ,medicine.drug_class ,Organic Chemistry ,Allosteric regulation ,Carboxamide ,Pharmacology ,Biochemistry ,03 medical and health sciences ,chemistry.chemical_compound ,030104 developmental biology ,0302 clinical medicine ,chemistry ,Drug Discovery ,Pyridine ,Toxicity ,medicine ,Potency ,Cholinergic ,030217 neurology & neurosurgery ,EC50 - Abstract
[Image: see text] 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 M(1) PAM potency (EC(50) = 230 nM, 93% ACh max), minimal M(1) agonist activity (agonist EC(50) > 10 μM), good CNS penetration (rat brain/plasma K(p) = 0.28, K(p,uu) = 0.32; mouse K(p) = 0.16, K(p,uu) = 0.18), and no cholinergic adverse events (AEs, e.g., seizures). This work demonstrates that within a chemical series prone to robust M(1) ago-PAM activity, SAR can result, which affords pure M(1) PAMs, devoid of cholinergic toxicity/seizure liability.
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- 2018
12. A Novel M1 PAM VU0486846 Exerts Efficacy in Cognition Models without Displaying Agonist Activity or Cholinergic Toxicity
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Jonathan W. Dickerson, Anna L. Blobaum, Jerri M. Rook, Kellie D. Nance, Colleen M. Niswender, Shaun R. Stauffer, Craig W. Lindsley, Joel M. Harp, Hyekyung P. Cho, Sean P. Moran, James Maksymetz, Pedro M. Garcia-Barrantes, P. Jeffrey Conn, Carrie K. Jones, Daniel H. Remke, Jeanette L. Bertron, and Sichen Chang
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0301 basic medicine ,Agonist ,Physiology ,medicine.drug_class ,Morpholines ,Cognitive Neuroscience ,Allosteric regulation ,Prefrontal Cortex ,CHO Cells ,Biochemistry ,Article ,Mice ,03 medical and health sciences ,Cognition ,Cricetulus ,0302 clinical medicine ,Allosteric Regulation ,Seizures ,Conditioning, Psychological ,Muscarinic acetylcholine receptor ,medicine ,Animals ,Cognitive Dysfunction ,Prefrontal cortex ,Receptor ,Chemistry ,Antagonist ,Fear ,Cell Biology ,General Medicine ,Risperidone ,Rats ,030104 developmental biology ,Exploratory Behavior ,Pyrazoles ,Cholinergic ,Neuroscience ,030217 neurology & neurosurgery ,Acetylcholine ,Antipsychotic Agents ,medicine.drug - Abstract
Selective activation of the M(1) subtype of muscarinic acetylcholine receptor, via positive allosteric modulation (PAM), is an exciting strategy to improve cognition in schizophrenia and Alzheimer’s disease patients. However, highly potent M(1) ago-PAMs, such as MK-7622, PF-06764427, and PF-06827443, can engender excessive activation of M(1), leading to agonist actions in the prefrontal cortex (PFC) that impair cognitive function, induce behavioral convulsions, and result in other classic cholinergic adverse events (AEs). Here, we report a fundamentally new and highly selective M(1) PAM, VU0486846. VU0486846 possesses only weak agonist activity in M(1)-expressing cell lines with high receptor reserve and is devoid of agonist actions in the PFC, unlike previously reported ago-PAMs MK-7622, PF-06764427, and PF-06827443. Moreover, VU0486846 shows no interaction with antagonist binding at the orthosteric acetylcholine (ACh) site (e.g., neither bitopic nor displaying negative cooperativity with [(3)H]-NMS binding at the orthosteric site), no seizure liability at high brain exposures, and no cholinergic AEs. However, as opposed to ago-PAMs, VU0486846 produces robust efficacy in the novel object recognition model of cognitive function. Importantly, we show for the first time that an M(1) PAM can reverse the cognitive deficits induced by atypical antipsychotics, such as risperidone. These findings further strengthen the argument that compounds with modest in vitro M(1) PAM activity (EC(50) > 100 nM) and pure-PAM activity in native tissues display robust procognitive efficacy without AEs mediated by excessive activation of M(1). Overall, the combination of compound assessment with recombinant in vitro assays (mindful of receptor reserve), native tissue systems (PFC), and phenotypic screens (behavioral convulsions) is essential to fully understand and evaluate lead compounds and enhance success in clinical development.
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- 2018
13. Discovery and Optimization of Potent and CNS Penetrant M5-Preferring Positive Allosteric Modulators Derived from a Novel, Chiral N-(Indanyl)piperidine Amide Scaffold
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Kellie D. Nance, Colleen M. Niswender, Christopher J. Langmead, Aaron M. Bender, Hyekyung P. Cho, Karl R. Voigtritter, P. Jeffrey Conn, Carrie K. Jones, Thomas M. Bridges, Sichen Chang, Patrick R. Gentry, Vincent B. Luscombe, Kaelyn S. Lingenfelter, Alice E. Berizzi, Jordan C. O’Neill, Craig W. Lindsley, Arthur Christopoulos, Charles W. Locuson, Patrick M. Sexton, and Xiaoyan Zhan
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0301 basic medicine ,Allosteric modulator ,Physiology ,Stereochemistry ,Cognitive Neuroscience ,Allosteric regulation ,Cell Biology ,General Medicine ,Biochemistry ,Small molecule ,03 medical and health sciences ,chemistry.chemical_compound ,030104 developmental biology ,0302 clinical medicine ,stomatognathic system ,chemistry ,Amide ,parasitic diseases ,Muscarinic acetylcholine receptor ,Piperidine ,Selectivity ,Penetrant (biochemical) ,030217 neurology & neurosurgery - Abstract
The pharmacology of the M5 muscarinic acetylcholine receptor (mAChR) is the least understood of the five mAChR subtypes due to a historic lack of selective small molecule tools. To address this shortcoming, we have continued the optimization effort around the prototypical M5 positive allosteric modulator (PAM) ML380 and have discovered and optimized a new series of M5 PAMs based on a chiral N-(indanyl)piperidine amide core with robust SAR, human and rat M5 PAM EC50 values
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- 2018
14. Genetic Reduction or Negative Modulation of mGlu7 Does Not Impact Anxiety and Fear Learning Phenotypes in a Mouse Model of MECP2 Duplication Syndrome
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P. Jeffrey Conn, Colleen M. Niswender, Branden J. Stansley, Nicole M. Fisher, Rocco G. Gogliotti, and Sheryl Anne D. Vermudez
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0301 basic medicine ,Genetics ,Physiology ,Cognitive Neuroscience ,Allosteric regulation ,Metabotropic glutamate receptor 7 ,MECP2 duplication syndrome ,Rett syndrome ,Cell Biology ,General Medicine ,Biology ,medicine.disease ,Biochemistry ,Phenotype ,MECP2 ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,mental disorders ,Gene duplication ,medicine ,Gene ,030217 neurology & neurosurgery - Abstract
Rett syndrome and MECP2 Duplication syndrome are neurodevelopmental disorders attributed to loss-of-function mutations in, or duplication of, the gene encoding methyl-CpG-binding protein 2 (MeCP2), respectively. We recently reported decreased expression and function of the metabotropic glutamate receptor 7 (mGlu7) in a mouse model of Rett syndrome. Positive allosteric modulation of mGlu7 activity was sufficient to improve several disease phenotypes including cognition. Here, we tested the hypothesis that mGlu7 expression would be reciprocally regulated in a mouse model of MECP2 Duplication syndrome, such that negative modulation of mGlu7 activity would exert therapeutic benefit. To the contrary, we report that mGlu7 is not functionally increased in mice overexpressing MeCP2 and that neither genetic nor pharmacological reduction of mGlu7 activity impacts phenotypes that are antiparallel to those observed in Rett syndrome model mice. These data expand our understanding of how mGlu7 expression and function i...
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- 2017
15. VU6010608, a Novel mGlu7 NAM from a Series of N-(2-(1H-1,2,4-Triazol-1-yl)-5-(trifluoromethoxy)phenyl)benzamides
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Colleen M. Niswender, Kevin M. McGowan, Carson W. Reed, Jerri M. Rook, Vincent B. Luscombe, Craig W. Lindsley, Annie L. Blobaum, Darren W. Engers, Matthew T. Loch, Hanna F. Roenfanz, P. Jeffrey Conn, Branden J. Stansley, Alice L. Rodriguez, Paul K. Spearing, Eileen M. Engelberg, and Daniel H. Remke
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0301 basic medicine ,03 medical and health sciences ,chemistry.chemical_compound ,030104 developmental biology ,0302 clinical medicine ,chemistry ,Stereochemistry ,Organic Chemistry ,Drug Discovery ,Benzamide ,Biochemistry ,030217 neurology & neurosurgery ,Cns penetration - Abstract
Herein, we report the structure–activity relationships within a series of mGlu7 NAMs based on an N-(2-(1H-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.
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- 2017
16. Discovery of VU6005649, a CNS Penetrant mGlu7/8 Receptor PAM Derived from a Series of Pyrazolo[1,5-a]pyrimidines
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Vincent B. Luscombe, Sichen Chang, Michael Bubser, Craig W. Lindsley, Joel M. Harp, Eileen M. Engelberg, Colleen M. Niswender, Darren W. Engers, P. Jeffrey Conn, Carrie K. Jones, Katrina A. Bollinger, Alice L. Rodriguez, Mabel Seto, Anna L. Blobaum, Rocco G. Gogliotti, Matthew T. Loch, and Masahito Abe
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0301 basic medicine ,Pyrimidine ,Chemistry ,Stereochemistry ,Organic Chemistry ,Contextual fear ,Biochemistry ,Cns penetration ,Receptor selectivity ,03 medical and health sciences ,chemistry.chemical_compound ,030104 developmental biology ,0302 clinical medicine ,In vivo ,Drug Discovery ,Receptor ,030217 neurology & neurosurgery - Abstract
Herein, we report the structure–activity relationships within a series of mGlu7 PAMs based on a pyrazolo[1,5-a]pyrimidine core with excellent CNS penetration (Kps > 1 and Kp,uus > 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.
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- 2017
17. Design and Synthesis of mGlu2 NAMs with Improved Potency and CNS Penetration Based on a Truncated Picolinamide Core
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Rebecca L. Weiner, Katrina A. Bollinger, Christopher J. Brassard, Hyekyung P. Cho, Julie L. Engers, Kyle A. Emmitte, Andrew S. Felts, Carrie K. Jones, Alice L. Rodriguez, Anna L. Blobaum, Craig W. Lindsley, P. Jeffrey Conn, Michael Bubser, Sichen Chang, and Colleen M. Niswender
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0301 basic medicine ,Allosteric modulator ,Chemistry ,Stereochemistry ,Organic Chemistry ,Penetration (firestop) ,Biochemistry ,Cns penetration ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Drug Discovery ,Potency ,Pet tracer ,030217 neurology & neurosurgery - Abstract
Herein, we detail the optimization of the mGlu2 negative allosteric modulator (NAM), VU6001192, by a reductionist approach to afford a novel, simplified mGlu2 NAM scaffold. This new chemotype not only affords potent and selective mGlu2 inhibition, as exemplified by VU6001966 (mGlu2 IC50 = 78 nM, mGlu3 IC50 > 30 μM), but also excellent central nervous system (CNS) penetration (Kp = 1.9, Kp,uu = 0.78), a feature devoid in all previously disclosed mGlu2 NAMs (Kps ≈ 0.3, Kp,uus ≈ 0.1). Moreover, this series, based on overall properties, represents an exciting lead series for potential mGlu2 PET tracer development.
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- 2017
18. Discovery of a Novel Series of Orally Bioavailable and CNS Penetrant Glucagon-like Peptide-1 Receptor (GLP-1R) Noncompetitive Antagonists Based on a 1,3-Disubstituted-7-aryl-5,5-bis(trifluoromethyl)-5,8-dihydropyrimido[4,5-d]pyrimidine-2,4(1H,3H)-dione Core
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Hyekyung P. Cho, Anna L. Blobaum, Kellie D. Nance, Colleen M. Niswender, Craig W. Lindsley, Tiffany D. Farmer, Emily Days, C. David Weaver, Anastasia G. Coldren, and Kevin D. Niswender
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0301 basic medicine ,endocrine system ,Trifluoromethyl ,Pyrimidine ,Insulin ,medicine.medical_treatment ,digestive, oral, and skin physiology ,Antagonist ,Pharmacology ,Glucagon-like peptide-1 ,03 medical and health sciences ,chemistry.chemical_compound ,030104 developmental biology ,Biochemistry ,chemistry ,In vivo ,Drug Discovery ,medicine ,Molecular Medicine ,Receptor ,Penetrant (biochemical) ,hormones, hormone substitutes, and hormone antagonists - Abstract
A duplexed, functional multiaddition high throughput screen and subsequent optimization effort identified the first orally bioavailable and CNS penetrant glucagon-like peptide-1 receptor (GLP-1R) noncompetitive antagonist. Antagonist 5d not only blocked exendin-4-stimulated insulin release in islets but also lowered insulin levels while increasing blood glucose in vivo.
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- 2017
19. Discovery of VU0467485/AZ13713945: An M4 PAM Evaluated as a Preclinical Candidate for the Treatment of Schizophrenia
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Mark E. Duggan, Michael W. Wood, Michael R. Wood, Craig W. Lindsley, Vincent B. Luscombe, Miguel A. Hurtado, Bruce J. Melancon, Alice L. Rodriguez, Thomas M. Bridges, Atin Lamsal, Michael Bubser, Anna L. Blobaum, Carrie K. Jones, Meredith J. Noetzel, Darren W. Engers, Sichen Chang, Michael S. Poslusney, P. Jeffrey Conn, Rebecca L. Weiner, Nicholas J. Brandon, Kellie D. Nance, and Colleen M. Niswender
- Subjects
0301 basic medicine ,Chemistry ,Organic Chemistry ,Allosteric regulation ,Pharmacology ,medicine.disease ,Biochemistry ,In vitro ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,In vivo ,Schizophrenia ,Drug Discovery ,Muscarinic acetylcholine receptor ,medicine ,Potency ,030217 neurology & neurosurgery - Abstract
Herein, we report the structure–activity relationships within a series of potent, selective, and orally bioavailable muscarinic acetylcholine receptor 4 (M4) 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.
- Published
- 2016
20. Development of Novel, CNS Penetrant Positive Allosteric Modulators for the Metabotropic Glutamate Receptor Subtype 1 (mGlu1), Based on an N-(3-Chloro-4-(1,3-dioxoisoindolin-2-yl)phenyl)-3-methylfuran-2-carboxamide Scaffold, That Potentiate Wild Type and Mutant mGlu1 Receptors Found in Schizophrenics
- Author
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Colleen M. Niswender, Hyekyung P. Cho, Jerri M. Rook, Anna L. Blobaum, P. Jeffrey Conn, Pedro M. Garcia-Barrantes, Zixiu Xiang, Craig W. Lindsley, Charles W. Locuson, and Frank W. Byers
- Subjects
Central Nervous System ,Receptor, Metabotropic Glutamate 5 ,Molecular Conformation ,Pharmacology ,Receptors, Metabotropic Glutamate ,Article ,Structure-Activity Relationship ,stomatognathic system ,parasitic diseases ,Drug Discovery ,Animals ,Humans ,GABA Modulators ,GABA Agonists ,Epilepsy ,Chemistry ,Metabotropic glutamate receptor 5 ,Metabotropic glutamate receptor 4 ,Metabotropic glutamate receptor 7 ,Rats ,Biochemistry ,Metabotropic glutamate receptor ,Schizophrenia ,Molecular Medicine ,Metabotropic glutamate receptor 1 ,Metabotropic glutamate receptor 3 ,Metabotropic glutamate receptor 2 ,Half-Life - Abstract
The therapeutic potential of selective mGlu1 activation is vastly unexplored relative to the other group I mGlu receptor, mGlu5; therefore, our lab has focused considerable effort toward developing mGlu1 positive allosteric modulators (PAMs) suitable as in vivo proof of concept tool compounds. Optimization of a series of mGlu1 PAMs based on an N-(3-chloro-4-(1,3-dioxoisoindolin-2-yl)phenyl)-3-methylfuran-2-carboxamide scaffold provided 17e, a potent (mGlu1 EC50 = 31.8 nM) and highly CNS penetrant (brain to plasma ratio (Kp) of 1.02) mGlu1 PAM tool compound, that potentiated not only wild-type human mGlu1 but also mutant mGlu1 receptors derived from deleterious GRM1 mutations found in schizophrenic patients. Moreover, both electrophysiological and in vivo studies indicate the mGlu1 ago-PAMs/PAMs do not possess the same epileptiform adverse effect liability as mGlu5 ago-PAMs/PAMs and maintain temporal activity suggesting a broader therapeutic window.
- Published
- 2015
21. 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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Zixiu Xiang, Corey R. Hopkins, Craig W. Lindsley, Michael R. Wood, Emily Days, Sean R. Bollinger, Karen J. Gregory, Francine Acher, L. Michelle Lewis, Darren W. Engers, P. Jeffrey Conn, Julie R. Field, Colleen M. Niswender, Margrith E. Mattmann, Bruce J. Melancon, C. David Weaver, Adam G. Walker, Rocio Zamorano, Rebecca Klar, Miguel A. Hurtado, Nidhi Jalan-Sakrikar, Thomas J. Utley, and Delphine Rigault
- Subjects
Male ,hippocampus ,Physiology ,Allosteric modulator ,Cognitive Neuroscience ,Glycine ,Glutamic Acid ,CHO Cells ,In Vitro Techniques ,Biology ,Pharmacology ,Receptors, Metabotropic Glutamate ,Transfection ,Benzoates ,Biochemistry ,Structure-Activity Relationship ,Cricetulus ,Animals ,Humans ,Pyrroles ,Excitatory Amino Acid Agents ,metabotropic glutamate receptor ,Thallium ,Picolinic Acids ,Dose-Response Relationship, Drug ,Metabotropic glutamate receptor 5 ,Metabotropic glutamate receptor 4 ,Metabotropic glutamate receptor 7 ,Metabotropic glutamate receptor 6 ,Excitatory Postsynaptic Potentials ,Cell Biology ,General Medicine ,electrophysiology ,Rats ,Mice, Inbred C57BL ,HEK293 Cells ,G Protein-Coupled Inwardly-Rectifying Potassium Channels ,Metabotropic glutamate receptor ,Metabotropic glutamate receptor 1 ,Acetanilides ,Calcium ,Metabotropic glutamate receptor 3 ,Propionates ,Metabotropic glutamate receptor 2 ,Neuroscience ,Research Article - 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
22. Development of a Highly Potent, Novel M5 Positive Allosteric Modulator (PAM) Demonstrating CNS Exposure: 1-((1H-Indazol-5-yl)sulfoneyl)-N-ethyl-N-(2-(trifluoromethyl)benzyl)piperidine-4-carboxamide (ML380)
- Author
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Colleen M. Niswender, Meredith J. Noetzel, Michael R. Wood, Patrick R. Gentry, Peter Chase, Masaya Kokubo, Thomas M. Bridges, Emery Smith, P. Jeffrey Conn, Atin Lamsal, Craig W. Lindsley, Peter Hodder, J. Scott Daniels, and Hyekyung P. Cho
- Subjects
Central Nervous System ,Male ,Indazoles ,Allosteric modulator ,Brief Article ,Stereochemistry ,medicine.drug_class ,Allosteric regulation ,Drug Evaluation, Preclinical ,Carboxamide ,Substrate Specificity ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Allosteric Regulation ,Piperidines ,Drug Discovery ,Muscarinic acetylcholine receptor ,medicine ,Animals ,Humans ,Potency ,030304 developmental biology ,Sulfonamides ,0303 health sciences ,Receptor, Muscarinic M5 ,Trifluoromethyl ,Chemistry ,Drug discovery ,High-Throughput Screening Assays ,Rats ,3. Good health ,Molecular Medicine ,Piperidine ,030217 neurology & neurosurgery - Abstract
A functional high throughput screen identified a novel chemotype for the positive allosteric modulation (PAM) of the muscarinic acetylcholine receptor (mAChR) subtype 5 (M5). Application of rapid analog, iterative parallel synthesis efficiently optimized M5 potency to arrive at the most potent M5 PAMs prepared to date and provided tool compound 8n (ML380) demonstrating modest CNS penetration (human M5 EC50 = 190 nM, rat M5 EC50 = 610 nM, brain to plasma ratio (Kp) of 0.36).
- Published
- 2014
23. Selective Activation of M4 Muscarinic Acetylcholine Receptors Reverses MK-801-Induced Behavioral Impairments and Enhances Associative Learning in Rodents
- Author
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Colleen M. Niswender, Carrie K. Jones, Michael R. Wood, Craig W. Lindsley, Frank W. Byers, Atin Lamsal, Bruce J. Melancon, Nicholas J. Brandon, John Dunlop, Mark E. Duggan, P. Jeffrey Conn, Ditte Dencker, James C. Tarr, Thomas M. Bridges, Michael S. Poslusney, J. Scott Daniels, Meredith J. Noetzel, Michael Grannan, Michael W. Wood, Robert W. Gould, Michael Bubser, and Jürgen Wess
- Subjects
Male ,Allosteric modulator ,Physiology ,Cognitive Neuroscience ,Cholinergic Agents ,Thiophenes ,Motor Activity ,Pharmacology ,VU0467154 ,Biochemistry ,Cell Line ,Rats, Sprague-Dawley ,Cricetulus ,Dogs ,Neurochemical ,Muscarinic acetylcholine receptor ,medicine ,Animals ,Humans ,Fear conditioning ,Amphetamine ,Mice, Knockout ,MK-801 ,Psychotropic Drugs ,Dose-Response Relationship, Drug ,Receptor, Muscarinic M4 ,Amphetamines ,Association Learning ,Brain ,Cell Biology ,General Medicine ,antipsychotic ,Rats ,Associative learning ,Mice, Inbred C57BL ,Pyridazines ,Macaca fascicularis ,M4 muscarinic ,Cholinergic ,NMDA receptor ,Central Nervous System Stimulants ,Dizocilpine Maleate ,cognitive enhancement ,Psychology ,Excitatory Amino Acid Antagonists ,Neuroscience ,Research Article ,medicine.drug - Abstract
Positive allosteric modulators (PAMs) of the M4 muscarinic acetylcholine receptor (mAChR) represent a novel approach for the treatment of psychotic symptoms associated with schizophrenia and other neuropsychiatric disorders. We recently reported that the selective M4 PAM VU0152100 produced an antipsychotic drug-like profile in rodents after amphetamine challenge. Previous studies suggest that enhanced cholinergic activity may also improve cognitive function and reverse deficits observed with reduced signaling through the N-methyl-d-aspartate subtype of the glutamate receptor (NMDAR) in the central nervous system. Prior to this study, the M1 mAChR subtype was viewed as the primary candidate for these actions relative to the other mAChR subtypes. Here we describe the discovery of a novel M4 PAM, VU0467154, with enhanced in vitro potency and improved pharmacokinetic properties relative to other M4 PAMs, enabling a more extensive characterization of M4 actions in rodent models. We used VU0467154 to test the hypothesis that selective potentiation of M4 receptor signaling could ameliorate the behavioral, cognitive, and neurochemical impairments induced by the noncompetitive NMDAR antagonist MK-801. VU0467154 produced a robust dose-dependent reversal of MK-801-induced hyperlocomotion and deficits in preclinical models of associative learning and memory functions, including the touchscreen pairwise visual discrimination task in wild-type mice, but failed to reverse these stimulant-induced deficits in M4 KO mice. VU0467154 also enhanced the acquisition of both contextual and cue-mediated fear conditioning when administered alone in wild-type mice. These novel findings suggest that M4 PAMs may provide a strategy for addressing the more complex affective and cognitive disruptions associated with schizophrenia and other neuropsychiatric disorders.
- Published
- 2014
24. Tetrahydronaphthyridine and Dihydronaphthyridinone Ethers As Positive Allosteric Modulators of the Metabotropic Glutamate Receptor 5 (mGlu5)
- Author
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Jason Manka, Hilde Lavreysen, Colleen M. Niswender, Jon Jacobs, M. Luz Martín-Martín, P. Jeffrey Conn, Meredith J. Noetzel, Han Min Tong, Elizabeth J. Herman, C. David Weaver, Chrysa Malosh, J. Scott Daniels, Susana Conde-Ceide, Paige N. Vinson, Shaun R. Stauffer, Gregor James Macdonald, Claire Mackie, José Manuel Bartolomé-Nebreda, Thomas Steckler, Silvia López, Craig W. Lindsley, Carrie K. Jones, Satyawan Jadhav, and Mark Turlington
- Subjects
Bicyclic molecule ,Metabotropic glutamate receptor 5 ,Stereochemistry ,Chemistry ,High-throughput screening ,Drug Discovery ,Allosteric regulation ,Antagonist ,Glutamate receptor ,Molecular Medicine ,Structure–activity relationship ,Linker - Abstract
Positive allosteric modulators (PAMs) of metabotropic glutamate receptor 5 (mGlu5) represent a promising therapeutic strategy for the treatment of schizophrenia. Starting from an acetylene-based lead from high throughput screening, an evolved bicyclic dihydronaphthyridinone was identified. We describe further refinements leading to both dihydronaphthyridinone and tetrahydronaphthyridine mGlu5 PAMs containing an alkoxy-based linkage as an acetylene replacement. Exploration of several structural features including western pyridine ring isomers, positional amides, linker connectivity/position, and combinations thereof, reveal that these bicyclic modulators generally exhibit steep SAR and within specific subseries display a propensity for pharmacological mode switching at mGlu5 as well as antagonist activity at mGlu3. Structure–activity relationships within a dihydronaphthyridinone subseries uncovered 12c (VU0405372), a selective mGlu5 PAM with good in vitro potency, low glutamate fold-shift, acceptable DMPK ...
- Published
- 2014
25. 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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Colleen M. Niswender, Craig W. Lindsley, Daryl F. Venable, P. Jeffrey Conn, Alice L. Rodriguez, Kyle A. Emmitte, Hyekyung P. Cho, and Darren W. Engers
- Subjects
Allosteric modulator ,Physiology ,Cognitive Neuroscience ,Allosteric regulation ,Drug Evaluation, Preclinical ,Succinimides ,CHO Cells ,Biology ,Receptors, Metabotropic Glutamate ,Transfection ,Biochemistry ,Fluorescence ,Cell Line ,chemistry.chemical_compound ,Cricetulus ,Species Specificity ,Succinimide ,Animals ,Humans ,Amino Acid Sequence ,Excitatory Amino Acid Agents ,Receptor ,HEK 293 cells ,Glutamate receptor ,Cell Biology ,General Medicine ,High-Throughput Screening Assays ,Rats ,HEK293 Cells ,Metabotropic receptor ,chemistry ,Metabotropic glutamate receptor ,Mutation ,Calcium - 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
26. Discovery of the First M5-Selective and CNS Penetrant Negative Allosteric Modulator (NAM) of a Muscarinic Acetylcholine Receptor: (S)-9b-(4-Chlorophenyl)-1-(3,4-difluorobenzoyl)-2,3-dihydro-1H-imidazo[2,1-a]isoindol-5(9bH)-one (ML375)
- Author
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Peter Chase, Thomas M. Bridges, Nathan R. Kett, Colleen M. Niswender, Patrick R. Gentry, Peter Hodder, Michael R. Wood, Masaya Kokubo, J. Scott Daniels, P. Jeffrey Conn, Hyekyung P. Cho, Emery Smith, Craig W. Lindsley, and Joel M. Harp
- Subjects
Allosteric modulator ,biology ,Stereochemistry ,Chemistry ,Drug discovery ,Allosteric regulation ,Pharmacology ,biology.organism_classification ,Drug Discovery ,Muscarinic acetylcholine receptor ,Molecular Medicine ,Structure–activity relationship ,Cricetulus ,Receptor ,IC50 - Abstract
A functional high throughput screen and subsequent multidimensional, iterative parallel synthesis effort identified the first muscarinic acetylcholine receptor (mAChR) negative allosteric modulator (NAM) selective for the M5 subtype. ML375 is a highly selective M5 NAM with submicromolar potency (human M5 IC50 = 300 nM, rat M5 IC50 = 790 nM, M1–M4 IC50 > 30 μM), excellent multispecies PK, high CNS penetration, and enantiospecific inhibition.
- Published
- 2013
27. Exploration of Allosteric Agonism Structure–Activity Relationships within an Acetylene Series of Metabotropic Glutamate Receptor 5 (mGlu5) Positive Allosteric Modulators (PAMs): Discovery of 5-((3-Fluorophenyl)ethynyl)-N-(3-methyloxetan-3-yl)picolinamide (ML254)
- Author
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Jerri M. Rook, Colleen M. Niswender, Thomas M. Bridges, Jens Meiler, Rocco D. Gogliotti, Karen J. Gregory, J. Scott Daniels, Ya Zhou, Kiran K. Gogi, Paige N. Vinson, P. Jeffrey Conn, Zixiu Xiang, Carrie K. Jones, Shaun R. Stauffer, Aspen Chun, Elizabeth Dong Nguyen, Craig W. Lindsley, Mark Turlington, and Meredith J. Noetzel
- Subjects
Metabotropic glutamate receptor 5 ,Chemistry ,Stereochemistry ,Allosteric regulation ,Glutamate receptor ,Neurotoxicity ,Cooperativity ,Ligand (biochemistry) ,medicine.disease ,stomatognathic system ,embryonic structures ,parasitic diseases ,Drug Discovery ,medicine ,Molecular Medicine ,Structure–activity relationship ,Metabotropic glutamate receptor 2 - Abstract
Positive allosteric modulators (PAMs) of metabotropic glutamate receptor 5 (mGlu5) represent a promising therapeutic strategy for the treatment of schizophrenia. Both allosteric agonism and high glutamate fold-shift have been implicated in the neurotoxic profile of some mGlu5 PAMs; however, these hypotheses remain to be adequately addressed. To develop tool compounds to probe these hypotheses, the structure-activity relationship of allosteric agonism was examined within an acetylenic series of mGlu5 PAMs exhibiting allosteric agonism in addition to positive allosteric modulation (ago-PAMs). PAM 38t, a low glutamate fold-shift allosteric ligand (maximum fold-shift ~ 3.0), was selected as a potent PAM with no agonism in the in vitro system used for compound characterization and in two native electrophysiological systems using rat hippocampal slices. PAM 38t (ML254) will be useful to probe the relative contribution of cooperativity and allosteric agonism to the adverse effect liability and neurotoxicity associated with this class of mGlu5 PAMs.
- Published
- 2013
28. ML297 (VU0456810), the First Potent and Selective Activator of the GIRK Potassium Channel, Displays Antiepileptic Properties in Mice
- Author
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Gary A. Sulikowski, C. David Weaver, Bende Zou, Emily Days, Liya Yang, Jerod S. Denton, Greg Sliwoski, Conrado Pascual, Adam Malik, Colleen M. Niswender, Ian M. Romaine, Ryan D. Morrison, Craig W. Lindsley, Xinmin Simon Xie, Kristian Kaufmann, J. Scott Daniels, and Yu Du
- Subjects
Patch-Clamp Techniques ,Physiology ,G protein ,Cognitive Neuroscience ,Drug Evaluation, Preclinical ,Receptors, Metabotropic Glutamate ,Biochemistry ,Mice ,Seizures ,Animals ,Humans ,Calcium Signaling ,G protein-coupled inwardly-rectifying potassium channel ,Patch clamp ,Ion channel ,Calcium signaling ,Electroshock ,Dose-Response Relationship, Drug ,Molecular Structure ,urogenital system ,Chemistry ,Inward-rectifier potassium ion channel ,Activator (genetics) ,Phenylurea Compounds ,Valproic Acid ,Cell Biology ,General Medicine ,Recombinant Proteins ,Potassium channel ,High-Throughput Screening Assays ,Rats ,HEK293 Cells ,G Protein-Coupled Inwardly-Rectifying Potassium Channels ,Microsomes, Liver ,Pentylenetetrazole ,Pyrazoles ,Anticonvulsants ,Neuroscience ,Injections, Intraperitoneal - Abstract
The G-protein activated, inward-rectifying potassium (K(+)) channels, "GIRKs", are a family of ion channels (Kir3.1-Kir3.4) that has been the focus of intense research interest for nearly two decades. GIRKs are comprised of various homo- and heterotetrameric combinations of four different subunits. These subunits are expressed in different combinations in a variety of regions throughout the central nervous system and in the periphery. The body of GIRK research implicates GIRK in processes as diverse as controlling heart rhythm, to effects on reward/addiction, to modulation of response to analgesics. Despite years of GIRK research, very few tools exist to selectively modulate GIRK channels' activity and until now no tools existed that potently and selectively activated GIRKs. Here we report the development and characterization of the first truly potent, effective, and selective GIRK activator, ML297 (VU0456810). We further demonstrate that ML297 is active in two in vivo models of epilepsy, a disease where up to 40% of patients remain with symptoms refractory to present treatments. The development of ML297 represents a truly significant advancement in our ability to selectively probe GIRK's role in physiology as well as providing the first tool for beginning to understand GIRK's potential as a target for a diversity of therapeutic indications.
- Published
- 2013
29. Substituted 1-Phenyl-3-(pyridin-2-yl)urea Negative Allosteric Modulators of mGlu5: Discovery of a New Tool Compound VU0463841 with Activity in Rat Models of Cocaine Addiction
- Author
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Craig W. Lindsley, Frank W. Byers, P. Jeffrey Conn, Daryl F. Venable, Andrew S. Felts, Ryan D. Morrison, Carrie K. Jones, Kyle A. Emmitte, Colleen M. Niswender, Russell J. Amato, Alice L. Rodriguez, and J. Scott Daniels
- Subjects
Allosteric modulator ,Physiology ,Receptor, Metabotropic Glutamate 5 ,Cognitive Neuroscience ,medicine.medical_treatment ,media_common.quotation_subject ,Central nervous system ,Allosteric regulation ,Aminopyridines ,Pharmacology ,Biochemistry ,Cocaine-Related Disorders ,Structure-Activity Relationship ,Allosteric Regulation ,medicine ,Animals ,Urea ,Structure–activity relationship ,Receptor ,media_common ,Chemistry ,Phenylurea Compounds ,Addiction ,Brain ,Cell Biology ,General Medicine ,Rats ,Stimulant ,Disease Models, Animal ,medicine.anatomical_structure ,Liver ,Metabotropic glutamate receptor ,Neuroscience - Abstract
Cocaine is a powerful and highly addictive stimulant that disrupts the normal reward circuitry in the central nervous system (CNS), producing euphoric effects. Cocaine use can lead to acute and life threatening emergencies, and abuse is associated with increased risk for contracting infectious diseases. Though certain types of behavioral therapy have proven effective for treatment of cocaine addiction, relapse remains high, and there are currently no approved medications for the treatment of cocaine abuse. Evidence has continued to accumulate that indicates a critical role for the metabotropic glutamate receptor subtype 5 (mGlu5) in the modulation of neural circuitry associated with the addictive properties of cocaine. While the small molecule mGlu5 negative allosteric modulator (NAM) field is relatively advanced, investigation into the potential of small molecule mGlu5 NAMs for the treatment of cocaine addiction remains an area of high interest. Herein we describe the discovery and characterization of a potent and selective compound 29 (VU0463841) with good CNS exposure in rats. The utility of 29 (VU0463841) was demonstrated by its ability to attenuate drug seeking behaviors in relevant rat models of cocaine addiction.
- Published
- 2013
30. Chemical Modification of the M1 Agonist VU0364572 Reveals Molecular Switches in Pharmacology and a Bitopic Binding Mode
- Author
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Gregory J. Digby, Michael R. Wood, P. Jeffrey Conn, Douglas J. Sheffler, Craig W. Lindsley, Evan P. Lebois, Colleen M. Niswender, Atin Lamsal, Christian Sevel, Thomas M. Bridges, and Thomas J. Utley
- Subjects
Agonist ,Physiology ,Stereochemistry ,medicine.drug_class ,Cognitive Neuroscience ,Allosteric regulation ,CHO Cells ,Muscarinic Agonists ,Pharmacology ,Ligands ,Biochemistry ,Allosteric Regulation ,Cricetinae ,Muscarinic acetylcholine receptor ,medicine ,Radioligand ,Animals ,Receptor ,G protein-coupled receptor ,Molecular switch ,Chemistry ,Biphenyl Compounds ,Receptor, Muscarinic M1 ,Cell Biology ,General Medicine ,Rats ,Biphenyl compound ,Benzamides ,Allosteric Site - Abstract
We previously reported the discovery of VU0364572 and VU0357017 as M(1)-selective agonists that appear to activate M(1) through actions at an allosteric site. Previous studies have revealed that chemical scaffolds for many allosteric modulators contain molecular switches that allow discovery of allosteric antagonists and allosteric agonists or positive allosteric modulators (PAMs) based on a single chemical scaffold. Based on this, we initiated a series of studies to develop selective M(1) allosteric antagonists based on the VU0364572 scaffold. Interestingly, two lead antagonists identified in this series, VU0409774 and VU0409775, inhibited ACh-induced Ca(2+) responses at rat M(1-5) receptor subtypes, suggesting they are nonselective muscarinic antagonists. VU0409774 and VU0409775 also completely displaced binding of the nonselective radioligand [(3)H]-NMS at M(1) and M(3) mAChRs with affinities similar to their functional IC(50) values. Finally, Schild analysis revealed that these compounds inhibit M(1) responses through a fully competitive interaction at the orthosteric binding site. This surprising finding prompted further studies to determine whether agonist activity of VU0364572 and VU0357017 may also engage in previously unappreciated actions at the orthosteric site on M(1). Surprisingly, both VU0364572 and VU0357017 completely displaced [(3)H]-NMS binding to the orthosteric site of M(1)-M(5) receptors at high concentrations. Furthermore, evaluation of agonist activity in systems with varying levels of receptor reserve and Furchgott analysis using a cell line expressing M(1) under control of an inducible promotor was consistent with an action of these compounds as weak orthosteric partial agonists of M(1). However, consistent with previous studies suggesting actions at a site that is distinct from the orthosteric binding site, VU0364572 or VU0357017 slowed the rate of [(3)H]-NMS dissociation from CHO-rM(1) membranes. Together, these results suggest that VU0364572 and VU0357017 act as bitopic ligands and that novel antagonists in this series act as competitive orthosteric site antagonists.
- Published
- 2012
31. 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 (mGlu4) with Oral Efficacy in an Antiparkinsonian Animal Model
- Author
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Colleen M. Niswender, Julie R. Field, Corey R. Hopkins, Darren W. Engers, Satyawan Jadhav, Jim Bogenpohl, Rocio Zamorano, Rocco D. Gogliotti, C. David Weaver, Analisa D. Thompson, Craig W. Lindsley, P. Jeffrey Conn, Carrie K. Jones, Ya Zhou, Yoland Smith, Anna L. Blobaum, Stacey R. Lindsley, J. Scott Daniels, and Ryan D. Morrison
- Subjects
Allosteric modulator ,biology ,Chemistry ,Metabotropic glutamate receptor 4 ,Allosteric regulation ,Catalepsy ,Pharmacology ,medicine.disease ,biology.organism_classification ,Drug Discovery ,medicine ,Haloperidol ,Molecular Medicine ,Structure–activity relationship ,Potency ,Cricetulus ,medicine.drug - Abstract
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.
- Published
- 2011
32. Solution-Phase Parallel Synthesis and SAR of Homopiperazinyl Analogs as Positive Allosteric Modulators of mGlu4
- Author
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Annie L. Blobaum, C. David Weaver, Rocio Zamorano, Craig W. Lindsley, Corey R. Hopkins, Yiu-Yin Cheung, P. Jeffrey Conn, and Colleen M. Niswender
- Subjects
Molecular Structure ,Extramural ,Metabotropic glutamate receptor 5 ,Stereochemistry ,Chemistry ,Metabotropic glutamate receptor 4 ,Allosteric regulation ,General Chemistry ,General Medicine ,Receptors, Metabotropic Glutamate ,Critical research ,Solution phase ,Article ,Piperazines ,Structure-Activity Relationship ,Allosteric Regulation ,Humans ,Structure–activity relationship ,Metabotropic glutamate receptor 2 - Abstract
Using a functional high-throughput screening (HTS) and subsequent solution-phase parallel synthesis approach, we have discovered a novel series of positive allosteric modulators for mGlu₄, a G-protein coupled receptor. This series is comprised of a homopiperazine central core. The solution-phase parallel synthesis and SAR of analogs derived from this series will be presented. This series of positive allosteric modulators of mGlu₄ provide critical research tools to further probe the mGlu₄-mediated effects in Parkinson's disease.
- Published
- 2011
33. Discovery of a Novel Chemical Class of mGlu5 Allosteric Ligands with Distinct Modes of Pharmacology
- Author
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Colleen M. Niswender, Craig W. Lindsley, Karen J. Gregory, P. Jeffrey Conn, Alice L. Rodriguez, Steven D. Townsend, and Alexis S. Hammond
- Subjects
Allosteric modulator ,Physiology ,Stereochemistry ,Cognitive Neuroscience ,Allosteric regulation ,glutamate ,Biology ,Pharmacology ,metabotropic ,Biochemistry ,allosteric ,03 medical and health sciences ,0302 clinical medicine ,heterocyclic compounds ,030304 developmental biology ,0303 health sciences ,Glutamate receptor ,potentiator ,Cell Biology ,General Medicine ,Potentiator ,Metabotropic receptor ,Metabotropic glutamate receptor ,mGlu5 ,030217 neurology & neurosurgery ,Research Article - Abstract
We previously discovered a positive allosteric modulator (PAM) of the metabotropic glutamate receptor subtype 5 (mGlu(5)) termed 4 N-{4-chloro-2-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]phenyl}-2-hydroxybenzamide (CPPHA) that elicits receptor activation through a novel allosteric site on mGlu(5), distinct from the classical mGlu(5) negative allosteric modulator (NAM) MPEP allosteric site. However, a shallow structure-activity relationship (SAR), poor physiochemical properties, and weak PAM activity at rat mGlu(5) limited the utility of CPPHA to explore allosteric activation of mGlu(5) at a non-MPEP site. Thus, we performed a functional high-throughput screen (HTS) and identified a novel mGlu(5) PAM benzamide scaffold, exemplified by VU0001850 (EC(50) = 1.3 μM, 106% Glu(max)) and VU0040237 (EC(50) = 350 nM, 84% Glu Max). An iterative parallel synthesis approach delivered 22 analogues, optimized mGlu(5) PAM activity to afford VU0357121 (EC(50) = 33 nM, 92% Glu(max)), and also revealed the first non-MPEP site neutral allosteric ligand (VU0365396). Like CPPHA, PAMs within this class do not appear to bind at the MPEP allosteric site based on radioligand binding studies. Moreover, mutagenesis studies indicate that VU0357121 and related analogues bind to a yet uncharacterized allosteric site on mGlu(5), distinct from CPPHA, yet share a functional interaction with the MPEP site.
- Published
- 2010
34. Re-exploration of the PHCCC Scaffold: Discovery of Improved Positive Allosteric Modulators of mGluR4
- Author
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Craig W. Lindsley, Corey R. Hopkins, Richard Williams, P. Jeffrey Conn, Ya Zhou, Colleen M. Niswender, and Qingwei Luo
- Subjects
Allosteric modulator ,Physiology ,Chemistry ,Metabotropic glutamate receptor ,Stereochemistry ,Cognitive Neuroscience ,Metabotropic glutamate receptor 4 ,Allosteric regulation ,Structure–activity relationship ,Cell Biology ,General Medicine ,Pharmacology ,Biochemistry - Abstract
This paper describes a detailed structure−activity relationship (SAR) analysis of the metabotropic glutamate receptor 4 (mGluR4) positive allosteric modulator, (−)-N-phenyl-7-(hydroxyimino)cyclopropa[b]chromen-1a-carboxamide (PHCCC). We have now developed compounds with improved potency and efficacy; in addition, compounds are presented that show selectivity for mGluR4 versus the other mGluR subtypes.
- Published
- 2010
35. Discovery and Characterization of Novel Subtype-Selective Allosteric Agonists for the Investigation of M1 Receptor Function in the Central Nervous System
- Author
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P. Jeffrey Conn, Satyawan Jadhav, Colleen M. Niswender, Jens Meiler, Craig W. Lindsley, Zixiu Xiang, Thomas M. Bridges, L. Michelle Lewis, Huiyong Yin, C. David Weaver, Carrie K. Jones, Alexander S. Kane, Eric S. Dawson, Evan P. Lebois, and J. Phillip Kennedy
- Subjects
Agonist ,Physiology ,medicine.drug_class ,Cognitive Neuroscience ,Mutagenesis ,Allosteric regulation ,Cell Biology ,General Medicine ,Muscarinic acetylcholine receptor M1 ,Biology ,Biochemistry ,Forebrain ,Muscarinic acetylcholine receptor ,medicine ,Cholinergic ,Neuroscience ,Function (biology) - Abstract
Cholinergic transmission in the forebrain is mediated primarily by five subtypes of muscarinic acetylcholine receptors (mAChRs), termed M(1)-M(5). Of the mAChR subtypes, M(1) is among the most heavily expressed in regions that are critical for learning and memory, and has been viewed as the most critical mAChR subtype for memory and attention mechanisms. Unfortunately, it has been difficult to develop selective activators of M(1) and other individual mAChR subtypes, which has prevented detailed studies of the functional roles of selective activation of M(1). Using a functional HTS screen and subsequent diversity-oriented synthesis approach we have discovered a novel series of highly selective M(1) allosteric agonists. These compounds activate M(1) with EC(50) values in the 150 nM to 500 nM range and have unprecedented, clean ancillary pharmacology (no substantial activity at 10μM across a large panel of targets). Targeted mutagenesis revealed a potentially novel allosteric binding site in the third extracellular loop of the M(1) receptor for these allosteric agonists. Optimized compounds, such as VU0357017, provide excellent brain exposure after systemic dosing and have robust in vivo efficacy in reversing scopolamine-induced deficits in a rodent model of contextual fear conditioning. This series of selective M(1) allosteric agonists provides critical research tools to allow dissection of M(1)-mediated effects in the CNS and potential leads for novel treatments for Alzheimer's disease and schizophrenia.
- Published
- 2009
36. Synthesis and Evaluation of a Series of Heterobiarylamides That Are Centrally Penetrant Metabotropic Glutamate Receptor 4 (mGluR4) Positive Allosteric Modulators (PAMs)
- Author
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Satyawan Jadhav, Corey R. Hopkins, P. Jeffrey Conn, Colleen M. Niswender, Rocio Zamorano, C. David Weaver, Darren W. Engers, Craig W. Lindsley, and Usha N. Menon
- Subjects
Metabotropic glutamate receptor 4 ,Allosteric regulation ,Pharmacology ,Receptors, Metabotropic Glutamate ,Amides ,Article ,Cell Line ,Rats ,Structure-Activity Relationship ,chemistry.chemical_compound ,Allosteric Regulation ,Biochemistry ,chemistry ,Drug Discovery ,Animals ,Humans ,Molecular Medicine ,Penetrant (biochemical) - Abstract
We report the synthesis and evaluation of a series of heterobiaryl amides as positive allosteric modulators of mGluR4. Compounds 9b and 9c showed submicromolar potency at both human and rat mGluR4. In addition, both 9b and 9c were shown to be centrally penetrant in rats using nontoxic vehicles, a major advance for the mGluR4 field.
- Published
- 2009
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