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Muscarinic M receptors modulate ethanol seeking in rats.
Berizzi AE, Perry CJ, Shackleford DM, Lindsley CW, Jones CK, Chen NA, Sexton PM, Christopoulos A, Langmead CJ, Lawrence AJ
(2018) Neuropsychopharmacology 43: 1510-1517
MeSH Terms: Animals, Conditioning, Operant, Corpus Striatum, Cues, Drug-Seeking Behavior, Ethanol, Imidazoles, Indoles, Locomotion, Male, Microinjections, Rats, Receptor, Muscarinic M5, Self Administration, Sucrose, Varenicline
Show Abstract · Added March 18, 2020
Despite the cost to both individual and society, alcohol use disorders (AUDs) remain a major health risk within society, and both relapse and heavy drinking are still poorly controlled with current medications. Here we demonstrate for the first time that a centrally active and selective negative allosteric modulator for the rat M muscarinic acetylcholine receptor (mAChR), ML375, decreases ethanol self-administration and attenuates cue-induced reinstatement of ethanol seeking in ethanol-preferring (iP) rats. Importantly, ML375 did not affect sucrose self-administration or general locomotor activity indicative of a selective effect on ethanol seeking. Based on the expression profile of M mAChRs in the brain and the distinct roles different aspects of the dorsal striatum have on long-term and short-term ethanol use, we studied whether intra-striatal microinjection of ML375 modulated ethanol intake in rats. We show in iP rats with an extensive history of ethanol intake that intra-dorsolateral (DL), but not intra-dorsomedial, striatal injections of ML375 reduced ethanol self-administration to a similar extent as the nicotinic acetylcholine receptor ligand varenicline, which has preclinical and clinical efficacy in reducing the reinforcing effects of ethanol. These data implicate the DL striatum as a locus for the effects of cholinergic-acting drugs on ethanol seeking in rats with a history of long-term ethanol use. Accordingly, we demonstrate in rats that selectively targeting the M mAChR can modulate both voluntary ethanol intake and cue-induced ethanol seeking and thereby provide direct evidence that the M mAChR is a potential novel target for pharmacotherapies aimed at treating AUDs.
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MeSH Terms
Selective inhibition of M muscarinic acetylcholine receptors attenuates cocaine self-administration in rats.
Gunter BW, Gould RW, Bubser M, McGowan KM, Lindsley CW, Jones CK
(2018) Addict Biol 23: 1106-1116
MeSH Terms: Animals, Behavior, Animal, Cocaine, Cocaine-Related Disorders, Conditioning, Operant, Disease Models, Animal, Dopamine Uptake Inhibitors, Dose-Response Relationship, Drug, Male, Mice, Rats, Rats, Sprague-Dawley, Receptor, Muscarinic M5, Reinforcement Schedule, Reward, Self Administration
Show Abstract · Added March 18, 2020
Cocaine use disorder (CUD) remains a debilitating health problem in the United States for which there are no Food and Drug Administration-approved treatment options. Accumulating anatomical and electrophysiological evidence indicates that the muscarinic acetylcholine receptor (mAChR) subtype 5 (M ) plays a critical role in the regulation of the mesolimbic dopaminergic reward circuitry, a major site of action for cocaine and other psychostimulants. In addition, M knockout mice exhibit reduced cocaine self-administration behaviors with no differences in sugar pellet-maintained responding relative to wild-type mice. These findings suggest that selective inhibition of M mAChR may provide a novel pharmacological approach for targeting CUD. Recently, we reported the synthesis and characterization of ML375, a selective negative allosteric modulator (NAM) for the rat and human M mAChR with optimized pharmacokinetic properties for systemic dosing in rodents. In the present study, male Sprague-Dawley rats were trained to self-administer intravenous cocaine (0.1-0.75 mg/kg/infusion) under a 10-response fixed ratio or a progressive ratio schedule of reinforcement. Under both schedules of reinforcement, ML375 produced dose-related reductions in cocaine self-administration. ML375 also modestly reduced sugar pellet-maintained responding on the 10-response, fixed ratio schedule but had no effect under a progressive ratio schedule of reinforcement. Further, ML375 did not affect general motor output as assessed by a rotarod test. Collectively, these results provide the first demonstration that selective inhibition of M using the M NAM ML375 can attenuate both the reinforcing effects and the relative strength of cocaine and suggest that M NAMs may represent a promising, novel treatment approach for CUD.
© 2017 Society for the Study of Addiction.
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MeSH Terms
Ligand-based virtual screen for the discovery of novel M5 inhibitor chemotypes.
Geanes AR, Cho HP, Nance KD, McGowan KM, Conn PJ, Jones CK, Meiler J, Lindsley CW
(2016) Bioorg Med Chem Lett 26: 4487-4491
MeSH Terms: Animals, CHO Cells, Cricetulus, Drug Discovery, Humans, Ligands, Muscarinic Antagonists, Quantitative Structure-Activity Relationship, Receptor, Muscarinic M5
Show Abstract · Added April 6, 2017
This Letter describes a ligand-based virtual screening campaign utilizing SAR data around the M5 NAMs, ML375 and VU6000181. Both QSAR and shape scores were employed to virtually screen a 98,000-member compound library. Neither approach alone proved productive, but a consensus score of the two models identified a novel scaffold which proved to be a modestly selective, but weak inhibitor (VU0549108) of the M5 mAChR (M5 IC50=6.2μM, M1-4 IC50s>10μM) based on an unusual 8-((1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl)-1-oxa-4-thia-8-azaspiro[4,5]decane scaffold. [(3)H]-NMS binding studies showed that VU0549108 interacts with the orthosteric site (Ki of 2.7μM), but it is not clear if this is negative cooperativity or orthosteric binding. Interestingly, analogs synthesized around VU0549108 proved weak, and SAR was very steep. However, this campaign validated the approach and warranted further expansion to identify additional novel chemotypes.
Copyright © 2016 Elsevier Ltd. All rights reserved.
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3 Members
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9 MeSH Terms
Further optimization of the M5 NAM MLPCN probe ML375: tactics and challenges.
Kurata H, Gentry PR, Kokubo M, Cho HP, Bridges TM, Niswender CM, Byers FW, Wood MR, Daniels JS, Conn PJ, Lindsley CW
(2015) Bioorg Med Chem Lett 25: 690-4
MeSH Terms: Allosteric Regulation, Animals, Brain, Half-Life, Humans, Imidazoles, Indoles, Microsomes, Liver, Protein Binding, Rats, Receptor, Muscarinic M5, Structure-Activity Relationship
Show Abstract · Added February 19, 2015
This Letter describes the continued optimization of the MLPCN probe ML375, a highly selective M5 negative allosteric modulator (NAM), through a combination of matrix libraries and iterative parallel synthesis. True to certain allosteric ligands, SAR was shallow, and the matrix library approach highlighted the challenges with M5 NAM SAR within in this chemotype. Once again, enantiospecific activity was noted, and potency at rat and human M5 were improved over ML375, along with slight enhancement in physiochemical properties, certain in vitro DMPK parameters and CNS distribution. Attempts to further enhance pharmacokinetics with deuterium incorporation afforded mixed results, but pretreatment with a pan-P450 inhibitor (1-aminobenzotriazole; ABT) provided increased plasma exposure.
Copyright © 2014 Elsevier Ltd. All rights reserved.
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12 MeSH Terms
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).
Gentry PR, Kokubo M, Bridges TM, Noetzel MJ, Cho HP, Lamsal A, Smith E, Chase P, Hodder PS, Niswender CM, Daniels JS, Conn PJ, Lindsley CW, Wood MR
(2014) J Med Chem 57: 7804-10
MeSH Terms: Allosteric Regulation, Animals, Central Nervous System, Drug Discovery, Drug Evaluation, Preclinical, High-Throughput Screening Assays, Humans, Indazoles, Male, Piperidines, Rats, Receptor, Muscarinic M5, Substrate Specificity, Sulfonamides
Show Abstract · Added February 19, 2015
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).
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2 Members
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14 MeSH Terms
Discovery, synthesis and characterization of a highly muscarinic acetylcholine receptor (mAChR)-selective M5-orthosteric antagonist, VU0488130 (ML381): a novel molecular probe.
Gentry PR, Kokubo M, Bridges TM, Cho HP, Smith E, Chase P, Hodder PS, Utley TJ, Rajapakse A, Byers F, Niswender CM, Morrison RD, Daniels JS, Wood MR, Conn PJ, Lindsley CW
(2014) ChemMedChem 9: 1677-82
MeSH Terms: Acetophenones, Animals, Drug Evaluation, Preclinical, Half-Life, Humans, Isoxazoles, Molecular Probes, Muscarinic Antagonists, Protein Binding, Rats, Receptor, Muscarinic M5
Show Abstract · Added February 19, 2015
Of the five G-protein-coupled muscarinic acetylcholine receptors (mAChRs; M1-M5), M5 is the least explored and understood due to a lack of mAChR subtype-selective ligands. We recently performed a high-throughput functional screen and identified a number of weak antagonist hits that are selective for the M5 receptor. Here, we report an iterative parallel synthesis and detailed molecular pharmacologic profiling effort that led to the discovery of the first highly selective, central nervous system (CNS)-penetrant M5-orthosteric antagonist, with sub-micromolar potency (hM5 IC50=450 nM, hM5 Ki=340 nM, M1-M4 IC50>30 μM), enantiospecific inhibition, and an acceptable drug metabolism and pharmacokinetics (DMPK) profile for in vitro and electrophysiology studies. This compound will be a powerful tool and molecular probe for the further investigation into the role of M5 in addiction and other diseases.
© 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
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11 MeSH Terms
M5 receptor activation produces opposing physiological outcomes in dopamine neurons depending on the receptor's location.
Foster DJ, Gentry PR, Lizardi-Ortiz JE, Bridges TM, Wood MR, Niswender CM, Sulzer D, Lindsley CW, Xiang Z, Conn PJ
(2014) J Neurosci 34: 3253-62
MeSH Terms: Animals, Animals, Newborn, Brain, CHO Cells, Calcium, Cricetulus, Dopamine, Dopaminergic Neurons, Dose-Response Relationship, Drug, In Vitro Techniques, Indoles, Membrane Potentials, Mice, Mice, Inbred C57BL, Mice, Knockout, Protein Binding, Rats, Rats, Sprague-Dawley, Receptor, Muscarinic M5, Transfection
Show Abstract · Added February 19, 2015
Of the five muscarinic receptor subtypes, the M5 receptor is the only one detectable in midbrain dopaminergic neurons, making it an attractive potential therapeutic target for treating disorders in which dopaminergic signaling is disrupted. However, developing an understanding of the role of M5 in regulating midbrain dopamine neuron function has been hampered by a lack of subtype-selective compounds. Here, we extensively characterize the novel compound VU0238429 and demonstrate that it acts as a positive allosteric modulator with unprecedented selectivity for the M5 receptor. We then used VU0238429, along with M5 knock-out mice, to elucidate the role of this receptor in regulating substantia nigra pars compacta (SNc) neuron physiology in both mice and rats. In sagittal brain slices that isolate the SNc soma from their striatal terminals, activation of muscarinic receptors induced Ca2+ mobilization and inward currents in SNc dopamine neurons, both of which were potentiated by VU0238429 and absent in M5 knock-out mice. Activation of M5 also increased the spontaneous firing rate of SNc neurons, suggesting that activation of somatodendritic M5 increases the intrinsic excitability of SNc neurons. However, in coronal slices of the striatum, potentiation of M5 with VU0238429 resulted in an inhibition in dopamine release as monitored with fast scan cyclic voltammetry. Accordingly, activation of M5 can lead to opposing physiological outcomes depending on the location of the receptor. Although activation of somatodendritic M5 receptors on SNc neurons leads to increased neuronal firing, activation of M5 receptors in the striatum induces an inhibition in dopamine release.
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2 Members
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20 MeSH Terms
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).
Gentry PR, Kokubo M, Bridges TM, Kett NR, Harp JM, Cho HP, Smith E, Chase P, Hodder PS, Niswender CM, Daniels JS, Conn PJ, Wood MR, Lindsley CW
(2013) J Med Chem 56: 9351-5
MeSH Terms: Allosteric Regulation, Animals, Brain, CHO Cells, Cricetinae, Cricetulus, Drug Discovery, Drug Evaluation, Preclinical, Humans, Imidazoles, Indoles, Male, Rats, Receptor, Muscarinic M5, Structure-Activity Relationship, Substrate Specificity
Show Abstract · Added January 30, 2015
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.
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3 Members
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16 MeSH Terms
Chemical lead optimization of a pan G(q) mAChR M(1), M(3), M(5) positive allosteric modulator (PAM) lead. Part I: Development of the first highly selective M(5) PAM.
Bridges TM, Kennedy JP, Cho HP, Breininger ML, Gentry PR, Hopkins CR, Conn PJ, Lindsley CW
(2010) Bioorg Med Chem Lett 20: 558-62
MeSH Terms: Allosteric Regulation, Animals, CHO Cells, Cricetinae, Cricetulus, Drug Design, High-Throughput Screening Assays, Mice, Mice, Knockout, Receptor, Muscarinic M1, Receptor, Muscarinic M3, Receptor, Muscarinic M5, Structure-Activity Relationship
Show Abstract · Added February 19, 2015
This Letter describes a chemical lead optimization campaign directed at VU0238429, the first M(5)-preferring positive allosteric modulator (PAM), discovered through analog work around VU0119498, a pan G(q) mAChR M(1), M(3), M(5) PAM. An iterative library synthesis approach delivered the first selective M(5) PAM (no activity at M(1)-M(4) @ 30microM), and an important tool compound to study the role of M(5) in the CNS.
Copyright 2009 Elsevier Ltd. All rights reserved.
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1 Members
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13 MeSH Terms
Discovery of the first highly M5-preferring muscarinic acetylcholine receptor ligand, an M5 positive allosteric modulator derived from a series of 5-trifluoromethoxy N-benzyl isatins.
Bridges TM, Marlo JE, Niswender CM, Jones CK, Jadhav SB, Gentry PR, Plumley HC, Weaver CD, Conn PJ, Lindsley CW
(2009) J Med Chem 52: 3445-8
MeSH Terms: Allosteric Regulation, Animals, CHO Cells, Cricetinae, Cricetulus, Isatin, Mice, Receptor, Muscarinic M5
Show Abstract · Added March 5, 2014
This report describes the discovery and initial characterization of the first positive allosteric modulator of muscarinic acetylcholine receptor subtype 5 (mAChR5 or M5). Functional HTS, identified VU0119498, which displayed micromolar potencies for potentiation of acetylcholine at M1, M3, and M5 receptors in cell-based Ca(2+) mobilization assays. Subsequent optimization led to the discovery of VU0238429, which possessed an EC(50) of approximately 1.16 microM at M5 with >30-fold selectivity versus M1 and M3, with no M2 or M4 potentiator activity.
1 Communities
4 Members
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8 MeSH Terms