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Biased M receptor-positive allosteric modulators reveal role of phospholipase D in M-dependent rodent cortical plasticity.
Moran SP, Xiang Z, Doyle CA, Maksymetz J, Lv X, Faltin S, Fisher NM, Niswender CM, Rook JM, Lindsley CW, Conn PJ
(2019) Sci Signal 12:
MeSH Terms: Allosteric Site, Animals, CHO Cells, Calcium, Cerebral Cortex, Cognition, Cricetinae, Cricetulus, Electrophysiology, Female, Humans, Long-Term Synaptic Depression, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Neuronal Plasticity, Phospholipase D, Prefrontal Cortex, Receptor, Muscarinic M1, Signal Transduction, Type C Phospholipases
Show Abstract · Added March 3, 2020
Highly selective, positive allosteric modulators (PAMs) of the M subtype of muscarinic acetylcholine receptor have emerged as an exciting new approach to potentially improve cognitive function in patients suffering from Alzheimer's disease and schizophrenia. Discovery programs have produced a structurally diverse range of M receptor PAMs with distinct pharmacological properties, including different extents of agonist activity and differences in signal bias. This includes biased M receptor PAMs that can potentiate coupling of the receptor to activation of phospholipase C (PLC) but not phospholipase D (PLD). However, little is known about the role of PLD in M receptor signaling in native systems, and it is not clear whether biased M PAMs display differences in modulating M-mediated responses in native tissue. Using PLD inhibitors and PLD knockout mice, we showed that PLD was necessary for the induction of M-dependent long-term depression (LTD) in the prefrontal cortex (PFC). Furthermore, biased M PAMs that did not couple to PLD not only failed to potentiate orthosteric agonist-induced LTD but also blocked M-dependent LTD in the PFC. In contrast, biased and nonbiased M PAMs acted similarly in potentiating M-dependent electrophysiological responses that were PLD independent. These findings demonstrate that PLD plays a critical role in the ability of M PAMs to modulate certain central nervous system (CNS) functions and that biased M PAMs function differently in brain regions implicated in cognition.
Copyright © 2019 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.
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2 Members
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22 MeSH Terms
Discovery of Tricyclic Triazolo- and Imidazopyridine Lactams as M Positive Allosteric Modulators.
Engers JL, Bender AM, Kalbfleisch JJ, Cho HP, Lingenfelter KS, Luscombe VB, Han C, Melancon BJ, Blobaum AL, Dickerson JW, Rook JM, Niswender CM, Emmitte KA, Conn PJ, Lindsley CW
(2019) ACS Chem Neurosci 10: 1035-1042
MeSH Terms: Allosteric Regulation, Animals, Drug Discovery, Humans, Imidazoles, Lactams, Mice, Muscarinic Agonists, Pyridines, Rats, Receptor, Muscarinic M1
Show Abstract · Added March 3, 2020
This Letter describes the chemical optimization of a new series of muscarinic acetylcholine receptor subtype 1 (M) positive allosteric modulators (PAMs) based on novel tricyclic triazolo- and imidazopyridine lactam cores, devoid of M agonism, e.g., no M ago-PAM activity, in high expressing recombinant cell lines. While all the new tricyclic congeners afforded excellent rat pharmacokinetic (PK) properties (CL < 8 mL/min/kg and t > 5 h), regioisomeric triazolopyridine analogues were uniformly not CNS penetrant ( K < 0.05), despite a lack of hydrogen bond donors. However, removal of a single nitrogen atom to afford imidazopyridine derivatives proved to retain the excellent rat PK and provide high CNS penetration ( K > 2), despite inclusion of a basic nitrogen. Moreover, 24c was devoid of M agonism in high expressing recombinant cell lines and did not induce cholinergic seizures in vivo in mice. Interestingly, all of the new M PAMs across the diverse tricyclic heterocyclic cores possessed equivalent CNS MPO scores (>4.5), highlighting the value of both "medicinal chemist's eye" and experimental data, e.g., not sole reliance (or decision bias) on in silico calculated properties, for parameters as complex as CNS penetration.
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11 MeSH Terms
The discovery of VU0486846: steep SAR from a series of M PAMs based on a novel benzomorpholine core.
Bertron JL, Cho HP, Garcia-Barrantes PM, Panarese JD, Salovich JM, Nance KD, Engers DW, Rook JM, Blobaum AL, Niswender CM, Stauffer SR, Conn PJ, Lindsley CW
(2018) Bioorg Med Chem Lett 28: 2175-2179
MeSH Terms: Animals, CHO Cells, Cricetulus, Drug Discovery, Humans, Molecular Structure, Morpholines, Pyrazoles, Rats, Receptor, Muscarinic M1, Structure-Activity Relationship
Show Abstract · Added March 3, 2020
This letter describes the chemical optimization of a new series of M positive allosteric modulators (PAMs) based on a novel benzomorpholine core, developed via iterative parallel synthesis, and culminating in the highly utilized rodent in vivo tool compound, VU0486846 (7), devoid of adverse effect liability. This is the first report of the optimization campaign (SAR and DMPK profiling) that led to the discovery of VU0486846 and details all of the challenges faced in allosteric modulator programs (both steep and flat SAR, as well as subtle structural changes affecting CNS penetration and overall physiochemical and DMPK properties).
Copyright © 2018 Elsevier Ltd. All rights reserved.
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2 Members
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MeSH Terms
PF-06827443 Displays Robust Allosteric Agonist and Positive Allosteric Modulator Activity in High Receptor Reserve and Native Systems.
Moran SP, Cho HP, Maksymetz J, Remke DH, Hanson RM, Niswender CM, Lindsley CW, Rook JM, Conn PJ
(2018) ACS Chem Neurosci 9: 2218-2224
MeSH Terms: Allosteric Regulation, Animals, CHO Cells, Calcium, Cricetulus, Dogs, Humans, Isoindoles, Mice, Oxazoles, Patch-Clamp Techniques, Prefrontal Cortex, Rats, Receptor, Muscarinic M1, Seizures
Show Abstract · Added March 3, 2020
Positive allosteric modulators (PAMs) of the M subtype of muscarinic acetylcholine receptor have attracted intense interest as an exciting new approach for improving the cognitive deficits in schizophrenia and Alzheimer's disease. Recent evidence suggests that the presence of intrinsic agonist activity of some M PAMs may reduce efficacy and contribute to adverse effect liability. However, the M PAM PF-06827443 was reported to have only weak agonist activity at human M receptors but produced M-dependent adverse effects. We now report that PF-06827443 is an allosteric agonist in cell lines expressing rat, dog, and human M and use of inducible cell lines shows that agonist activity of PF-06827443 is dependent on receptor reserve. Furthermore, PF-06827443 is an agonist in native tissue preparations and induces behavioral convulsions in mice similar to other ago-PAMs. These findings suggest that PF-06827443 is a robust ago-PAM, independent of species, in cell lines and native systems.
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MeSH Terms
M-positive allosteric modulators lacking agonist activity provide the optimal profile for enhancing cognition.
Moran SP, Dickerson JW, Cho HP, Xiang Z, Maksymetz J, Remke DH, Lv X, Doyle CA, Rajan DH, Niswender CM, Engers DW, Lindsley CW, Rook JM, Conn PJ
(2018) Neuropsychopharmacology 43: 1763-1771
MeSH Terms: Allosteric Regulation, Animals, CHO Cells, Cholinergic Agents, Cricetulus, Excitatory Postsynaptic Potentials, Male, Mice, Inbred C57BL, Nootropic Agents, Prefrontal Cortex, Pyramidal Cells, Rats, Rats, Sprague-Dawley, Receptor, Muscarinic M1, Recognition, Psychology, Tissue Culture Techniques
Show Abstract · Added March 3, 2020
Highly selective positive allosteric modulators (PAMs) of the M subtype of muscarinic acetylcholine receptor have emerged as an exciting new approach for improving cognitive function in patients suffering from Alzheimer's disease and schizophrenia. However, excessive activation of M is known to induce seizure activity and have actions in the prefrontal cortex (PFC) that could impair cognitive function. We now report a series of pharmacological, electrophysiological, and behavioral studies in which we find that recently reported M PAMs, PF-06764427 and MK-7622, have robust agonist activity in cell lines and agonist effects in the mouse PFC, and have the potential to overactivate the M receptor and disrupt PFC function. In contrast, structurally distinct M PAMs (VU0453595 and VU0550164) are devoid of agonist activity in cell lines and maintain activity dependence of M activation in the PFC. Consistent with the previously reported effect of PF-06764427, the ago-PAM MK-7622 induces severe behavioral convulsions in mice. In contrast, VU0453595 does not induce behavioral convulsions at doses well above those required for maximal efficacy in enhancing cognitive function. Furthermore, in contrast to the robust efficacy of VU0453595, the ago-PAM MK-7622 failed to improve novel object recognition, a rodent assay of cognitive function. These findings suggest that in vivo cognition-enhancing efficacy of M PAMs can be observed with PAMs lacking intrinsic agonist activity and that intrinsic agonist activity of M PAMs may contribute to adverse effects and reduced efficacy in improving cognitive function.
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MeSH Terms
M muscarinic activation induces long-lasting increase in intrinsic excitability of striatal projection neurons.
Lv X, Dickerson JW, Rook JM, Lindsley CW, Conn PJ, Xiang Z
(2017) Neuropharmacology 118: 209-222
MeSH Terms: Acetylcholine, Action Potentials, Animals, Channelrhodopsins, Choline O-Acetyltransferase, Cholinergic Agents, Corpus Striatum, Cues, Excitatory Amino Acid Antagonists, Excitatory Postsynaptic Potentials, Female, Gene Expression Regulation, Learning, Male, Mice, Mice, Inbred C57BL, Mice, Transgenic, Motor Activity, Neurons, Photic Stimulation, Receptor, Muscarinic M1
Show Abstract · Added April 6, 2017
The dorsolateral striatum is critically involved in movement control and motor learning. Striatal function is regulated by a variety of neuromodulators including acetylcholine. Previous studies have shown that cholinergic activation excites striatal principal projection neurons, medium spiny neurons (MSNs), and this action is mediated by muscarinic acetylcholine subtype 1 receptors (M) through modulating multiple potassium channels. In the present study, we used electrophysiology techniques in conjunction with optogenetic and pharmacological tools to determine the long-term effects of striatal cholinergic activation on MSN intrinsic excitability. A transient increase in acetylcholine release in the striatum by optogenetic stimulation resulted in a long-lasting increase in excitability of MSNs, which was associated with hyperpolarizing shift of action potential threshold and decrease in afterhyperpolarization (AHP) amplitude, leading to an increase in probability of EPSP-action potential coupling. The M selective antagonist VU0255035 prevented, while the M selective positive allosteric modulator (PAM) VU0453595 potentiated the cholinergic activation-induced persistent increase in MSN intrinsic excitability, suggesting that M receptors are critically involved in the induction of this long-lasting response. This M receptor-dependent long-lasting change in MSN intrinsic excitability could have significant impact on striatal processing and might provide a novel mechanism underlying cholinergic regulation of the striatum-dependent motor learning and cognitive function. Consistent with this, behavioral studies indicate that potentiation of M receptor signaling by VU0453595 enhanced performance of mice in cue-dependent water-based T-maze, a dorsolateral striatum-dependent learning task.
Copyright © 2017. Published by Elsevier Ltd.
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21 MeSH Terms
Diverse Effects on M Signaling and Adverse Effect Liability within a Series of M Ago-PAMs.
Rook JM, Abe M, Cho HP, Nance KD, Luscombe VB, Adams JJ, Dickerson JW, Remke DH, Garcia-Barrantes PM, Engers DW, Engers JL, Chang S, Foster JJ, Blobaum AL, Niswender CM, Jones CK, Conn PJ, Lindsley CW
(2017) ACS Chem Neurosci 8: 866-883
MeSH Terms: Allosteric Regulation, Animals, Drug Discovery, Humans, Mice, Muscarinic Agonists, Rats, Receptor, Muscarinic M1, Structure-Activity Relationship
Show Abstract · Added April 6, 2017
Both historical clinical and recent preclinical data suggest that the M muscarinic acetylcholine receptor is an exciting target for the treatment of Alzheimer's disease and the cognitive and negative symptom clusters in schizophrenia; however, early drug discovery efforts targeting the orthosteric binding site have failed to afford selective M activation. Efforts then shifted to focus on selective activation of M via either allosteric agonists or positive allosteric modulators (PAMs). While M PAMs have robust efficacy in rodent models, some chemotypes can induce cholinergic adverse effects (AEs) that could limit their clinical utility. Here, we report studies aimed at understanding the subtle structural and pharmacological nuances that differentiate efficacy from adverse effect liability within an indole-based series of M ago-PAMs. Our data demonstrate that closely related M PAMs can display striking differences in their in vivo activities, especially their propensities to induce adverse effects. We report the discovery of a novel PAM in this series that is devoid of observable adverse effect liability. Interestingly, the molecular pharmacology profile of this novel PAM is similar to that of a representative M PAM that induces severe AEs. For instance, both compounds are potent ago-PAMs that demonstrate significant interaction with the orthosteric site (either bitopic or negative cooperativity). However, there are subtle differences in efficacies of the compounds at potentiating M responses, agonist potencies, and abilities to induce receptor internalization. While these differences may contribute to the differential in vivo profiles of these compounds, the in vitro differences are relatively subtle and highlight the complexities of allosteric modulators and the need to focus on in vivo phenotypic screening to identify safe and effective M PAMs.
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4 Members
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9 MeSH Terms
Discovery and SAR of a novel series of potent, CNS penetrant M4 PAMs based on a non-enolizable ketone core: Challenges in disposition.
Wood MR, Noetzel MJ, Tarr JC, Rodriguez AL, Lamsal A, Chang S, Foster JJ, Smith E, Chase P, Hodder PS, Engers DW, Niswender CM, Brandon NJ, Wood MW, Duggan ME, Conn PJ, Bridges TM, Lindsley CW
(2016) Bioorg Med Chem Lett 26: 4282-6
MeSH Terms: Allosteric Regulation, Animals, Central Nervous System, Drug Discovery, Humans, Ketones, Molecular Structure, Receptor, Muscarinic M1, Structure-Activity Relationship
Show Abstract · Added April 6, 2017
This Letter describes the chemical optimization of a novel series of M4 PAMs based on a non-enolizable ketone core, identified from an MLPCN functional high-throughput screen. The HTS hit was potent, selective and CNS penetrant; however, the compound was highly cleared in vitro and in vivo. SAR provided analogs for which M4 PAM potency and CNS exposure were maintained; yet, clearance remained high. Metabolite identification studies demonstrated that this series was subject to rapid, and near quantitative, reductive metabolism to the corresponding secondary alcohol metabolite that was devoid of M4 PAM activity.
Copyright © 2016 Elsevier Ltd. All rights reserved.
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2 Members
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9 MeSH Terms
Further optimization of the M1 PAM VU0453595: Discovery of novel heterobicyclic core motifs with improved CNS penetration.
Panarese JD, Cho HP, Adams JJ, Nance KD, Garcia-Barrantes PM, Chang S, Morrison RD, Blobaum AL, Niswender CM, Stauffer SR, Conn PJ, Lindsley CW
(2016) Bioorg Med Chem Lett 26: 3822-5
MeSH Terms: Allosteric Regulation, Animals, Central Nervous System, Central Nervous System Agents, Dose-Response Relationship, Drug, Drug Discovery, Heterocyclic Compounds, Molecular Structure, Pyridines, Pyrroles, Rats, Receptor, Muscarinic M1, Structure-Activity Relationship
Show Abstract · Added April 6, 2017
This Letter describes the continued chemical optimization of the VU0453595 series of M1 positive allosteric modulators (PAMs). By surveying alternative 5,6- and 6,6-heterobicylic cores for the 6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-5-one core of VU453595, we found new cores that engendered not only comparable or improved M1 PAM potency, but significantly improved CNS distribution (Kps 0.3-3.1). Moreover, this campaign provided fundamentally distinct M1 PAM chemotypes, greatly expanding the available structural diversity for this valuable CNS target, devoid of hydrogen-bond donors.
Copyright © 2016 Elsevier Ltd. All rights reserved.
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2 Members
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13 MeSH Terms
M1 and M3 muscarinic receptors may play a role in the neurotoxicity of anhydroecgonine methyl ester, a cocaine pyrolysis product.
Garcia RC, Dati LM, Torres LH, da Silva MA, Udo MS, Abdalla FM, da Costa JL, Gorjão R, Afeche SC, Yonamine M, Niswender CM, Conn PJ, Camarini R, Sandoval MR, Marcourakis T
(2015) Sci Rep 5: 17555
MeSH Terms: Animals, Apoptosis, CHO Cells, Cocaine, Cricetinae, Cricetulus, DNA Fragmentation, Female, Hippocampus, Neurotoxicity Syndromes, Neurotoxins, Rats, Receptor, Muscarinic M1, Receptor, Muscarinic M3, Time Factors
Show Abstract · Added February 18, 2016
The smoke of crack cocaine contains cocaine and its pyrolysis product, anhydroecgonine methyl ester (AEME). AEME possesses greater neurotoxic potential than cocaine and an additive effect when they are combined. Since atropine prevented AEME-induced neurotoxicity, it has been suggested that its toxic effects may involve the muscarinic cholinergic receptors (mAChRs). Our aim is to understand the interaction between AEME and mAChRs and how it can lead to neuronal death. Using a rat primary hippocampal cell culture, AEME was shown to cause a concentration-dependent increase on both total [(3)H]inositol phosphate and intracellular calcium, and to induce DNA fragmentation after 24 hours of exposure, in line with the activation of caspase-3 previously shown. Additionally, we assessed AEME activity at rat mAChR subtypes 1-5 heterologously expressed in Chinese Hamster Ovary cells. l-[N-methyl-(3)H]scopolamine competition binding showed a preference of AEME for the M2 subtype; calcium mobilization tests revealed partial agonist effects at M1 and M3 and antagonist activity at the remaining subtypes. The selective M1 and M3 antagonists and the phospholipase C inhibitor, were able to prevent AEME-induced neurotoxicity, suggesting that the toxicity is due to the partial agonist effect at M1 and M3 mAChRs, leading to DNA fragmentation and neuronal death by apoptosis.
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2 Members
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15 MeSH Terms