| Reference | [1]. Neuropharmacology. 2018 Jan;128:492-502. doi: 10.1016/j.neuropharm.2017.07.013. Epub 2017 Jul 17.<br />
Cognitive enhancement and antipsychotic-like activity following repeated dosing with the selective M(4) PAM VU0467154.<br />
Gould RW(1), Grannan MD(1), Gunter BW(1), Ball J(2), Bubser M(1), Bridges TM(1), Wess J(3), Wood MW(4), Brandon NJ(4), Duggan ME(4), Niswender CM(5), Lindsley CW(6), Conn PJ(5), Jones CK(7).<br />
Author information: (1)Department of Pharmacology, Vanderbilt University, Nashville, TN 37232, USA; Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, TN 37232, USA. (2)Department of Pharmacology, Vanderbilt University, Nashville, TN 37232, USA. (3)Laboratory of Bioorganic Chemistry, NIDDK, National Institutes of Health, Bethesda, MD 20892, USA. (4)AstraZeneca, Neuroscience, Innovative Medicines & Early Development, Waltham, MA 02451, USA. (5)Department of Pharmacology, Vanderbilt University, Nashville, TN 37232, USA; Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, TN 37232, USA; Vanderbilt Kennedy Center, Nashville, TN 37232, USA. (6)Department of Pharmacology, Vanderbilt University, Nashville, TN 37232, USA; Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, TN 37232, USA; Department of Chemistry, Vanderbilt University, Nashville, TN 37232, USA. (7)Department of Pharmacology, Vanderbilt University, Nashville, TN 37232, USA; Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, TN 37232, USA. Electronic address: [email protected].<br />
Although selective activation of the M1 muscarinic acetylcholine receptor (mAChR) subtype has been shown to improve cognitive function in animal models of neuropsychiatric disorders, recent evidence suggests that enhancing M4 mAChR function can also improve memory performance. Positive allosteric modulators (PAMs) targeting the M4 mAChR subtype have shown therapeutic potential for the treatment of multiple symptoms observed in schizophrenia, including positive and cognitive symptoms when assessed in acute preclinical dosing paradigms. Since the cholinergic system has been implicated in multiple stages of learning and memory, we evaluated the effects of repeated dosing with the highly selective M4 PAM VU0467154 on either acquisition and/or consolidation of learning and memory when dosed alone or after pharmacologic challenge with the N-methyl-d-aspartate subtype of glutamate receptors (NMDAR) antagonist MK-801. MK-801 challenge represents a well-documented preclinical model of NMDAR hypofunction that is thought to underlie some of the positive and cognitive symptoms observed in schizophrenia. In wildtype mice, 10-day, once-daily dosing of VU0467154 either prior to, or immediately after daily testing enhanced the rate of learning in a touchscreen visual pairwise discrimination task; these effects were absent in M4 mAChR knockout mice. Following a similar 10-day, once-daily dosing regimen of VU0467154, we also observed 1) improved acquisition of memory in a cue-mediated conditioned freezing paradigm, 2) attenuation of MK-801-induced disruptions in the acquisition of memory in a context-mediated conditioned freezing paradigm and 3) reversal of MK-801-induced hyperlocomotion. Comparable efficacy and plasma and brain concentrations of VU0467154 were observed after repeated dosing as those previously reported with an acute, single dose administration of this M4 PAM. Together, these studies are the first to demonstrate that cognitive enhancing and antipsychotic-like activity are not subject to the development of tolerance following repeated dosing with a selective M4 PAM in mice and further suggest that activation of M4 mAChRs may modulate both acquisition and consolidation of memory functions.<br />
DOI: 10.1016/j.neuropharm.2017.07.013 PMCID: PMC6756753 PMID: 28729220 [Indexed for MEDLINE]<br />
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[2]. Bioorg Med Chem Lett. 2017 Jan 15;27(2):171-175. doi: 10.1016/j.bmcl.2016.11.086. Epub 2016 Nov 30.<br />
Challenges in the development of an M(4) PAM in vivo tool compound: The discovery of VU0467154 and unexpected DMPK profiles of close analogs.<br />
Wood MR(1), Noetzel MJ(2), Poslusney MS(3), Melancon BJ(2), Tarr JC(3), Lamsal A(3), Chang S(3), Luscombe VB(2), Weiner RL(2), Cho HP(2), Bubser M(3), Jones CK(4), Niswender CM(4), Wood MW(5), Engers DW(2), Brandon NJ(5), Duggan ME(5), Conn PJ(4), Bridges TM(6), Lindsley CW(7).<br />
Author information: (1)Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Department of Chemistry, Vanderbilt University, Nashville, TN 37232, USA. (2)Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA. (3)Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, TN 37232, USA. (4)Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA; Vanderbilt Kennedy Center, Vanderbilt University School of Medicine, Nashville, TN 37232, USA. (5)Neuroscience Innovative Medicines, Astra Zeneca, 141 Portland Street, Cambridge, MA 02139, USA. (6)Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA. Electronic address: [email protected]. (7)Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA; Department of Chemistry, Vanderbilt University, Nashville, TN 37232, USA. Electronic address: [email protected].<br />
This letter describes the chemical optimization of a novel series of M4 positive allosteric modulators (PAMs) based on a 5-amino-thieno[2,3-c]pyridazine core, developed via iterative parallel synthesis, and culminating in the highly utilized rodent in vivo tool compound, VU0467154 (5). This is the first report of the optimization campaign (SAR and DMPK profiling) that led to the discovery of VU0467154, and details all of the challenges faced in allosteric modulator programs (steep SAR, species differences in PAM pharmacology and subtle structural changes affecting CNS penetration).<br />
DOI: 10.1016/j.bmcl.2016.11.086 PMCID: PMC5340297 PMID: 27939174 [Indexed for MEDLINE]<br />
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[3]. Neuropharmacology. 2016 Mar;102:244-53. doi: 10.1016/j.neuropharm.2015.11.016. Epub 2015 Nov 23.<br />
State-dependent alterations in sleep/wake architecture elicited by the M4 PAM VU0467154 – Relation to antipsychotic-like drug effects.<br />
Gould RW(1), Nedelcovych MT(1), Gong X(2), Tsai E(2), Bubser M(1), Bridges TM(1), Wood MR(3), Duggan ME(4), Brandon NJ(4), Dunlop J(4), Wood MW(4), Ivarsson M(5), Noetzel MJ(1), Daniels JS(1), Niswender CM(1), Lindsley CW(3), Conn PJ(1), Jones CK(6).<br />
Author information: (1)Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, TN 37232, USA. (2)Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232, USA. (3)Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Department of Chemistry, Vanderbilt University, Nashville, TN 37232, USA. (4)Neuroscience Innovative Medicines, AstraZeneca, Cambridge, MA 02139, USA. (5)Proteostasis Therapeutics, 200 Technology Square, Cambridge, MA 02139, USA. (6)Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, TN 37232, USA. Electronic address: [email protected].<br />
Accumulating evidence indicates direct relationships between sleep abnormalities and the severity and prevalence of other symptom clusters in schizophrenia. Assessment of potential state-dependent alterations in sleep architecture and arousal relative to antipsychotic-like activity is critical for the development of novel antipsychotic drugs (APDs). Recently, we reported that VU0467154, a selective positive allosteric modulator (PAM) of the M4 muscarinic acetylcholine receptor (mAChR), exhibits robust APD-like and cognitive enhancing activity in rodents. However, the state-dependent effects of VU0467154 on sleep architecture and arousal have not been examined. Using polysomnography and quantitative electroencephalographic recordings from subcranial electrodes in rats, we evaluated the effects of VU0467154, in comparison with the atypical APD clozapine and the M1/M4-preferring mAChR agonist xanomeline. VU0467154 induced state-dependent alterations in sleep architecture and arousal including delayed Rapid Eye Movement (REM) sleep onset, increased cumulative duration of total and Non-Rapid Eye Movement (NREM) sleep, and increased arousal during waking periods. Clozapine decreased arousal during wake, increased cumulative NREM, and decreased REM sleep. In contrast, xanomeline increased time awake and arousal during wake, but reduced slow wave activity during NREM sleep. Additionally, in combination with the N-methyl-d-aspartate subtype of glutamate receptor (NMDAR) antagonist MK-801, modeling NMDAR hypofunction thought to underlie many symptoms in schizophrenia, both VU0467154 and clozapine attenuated MK-801-induced elevations in high frequency gamma power consistent with an APD-like mechanism of action. These findings suggest that selective M4 PAMs may represent a novel mechanism for treating multiple symptoms of schizophrenia, including disruptions in sleep architecture without a sedative profile.<br />
DOI: 10.1016/j.neuropharm.2015.11.016 PMCID: PMC4809053 PMID: 26617071 [Indexed for MEDLINE]<br />
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[4]. Biol Psychiatry. 2020 Dec 15;88(12):898-909. doi: 10.1016/j.biopsych.2020.02.019. Epub 2020 Feb 29.<br />
Acetylcholine Muscarinic M(4) Receptors as a Therapeutic Target for Alcohol Use Disorder: Converging Evidence From Humans and Rodents.<br />
Walker LC(1), Berizzi AE(2), Chen NA(1), Rueda P(2), Perreau VM(1), Huckstep K(1), Srisontiyakul J(3), Govitrapong P(3), Xiaojian J(4), Lindsley CW(5), Jones CK(5), Riddy DM(2), Christopoulos A(2), Langmead CJ(6), Lawrence AJ(7).<br />
Author information: (1)Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, Victoria, Australia. (2)Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia. (3)Research Center for Neuroscience, Institute of Molecular Biosciences, Mahidol University, Salaya, Nakhon Pathom, Thailand. (4)Shenzhen Kangning Hospital, Shenzhen University Health Science Center, Shenzhen, China; Shenzhen Mental Health Center, Shenzhen University Health Science Center, Shenzhen, China. (5)Department of Pharmacology, Vanderbilt Center for Neuroscience and Drug Discovery, Vanderbilt University, Nashville, Tennessee; Department of Chemistry, Vanderbilt Center for Neuroscience and Drug Discovery, Vanderbilt University, Nashville, Tennessee. (6)Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia. Electronic address: [email protected]. (7)Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, Victoria, Australia. Electronic address: [email protected].<br />
Comment in Biol Psychiatry. 2020 Dec 15;88(12):891-892.<br />
BACKGROUND: Alcohol use disorder (AUD) is a major socioeconomic burden on society, and current pharmacotherapeutic treatment options are inadequate. Aberrant alcohol use and seeking alters frontostriatal function. METHODS: We performed genome-wide RNA sequencing and subsequent quantitative polymerase chain reaction and receptor binding validation in the caudate-putamen of human AUD samples to identify potential therapeutic targets. We then back-translated our top candidate targets into a rodent model of long-term alcohol consumption to assess concordance of molecular adaptations in the rat striatum. Finally, we adopted rat behavioral models of alcohol intake and seeking to validate a potential therapeutic target. RESULTS: We found that G protein-coupled receptors were the top canonical pathway differentially regulated in individuals with AUD. The M4 muscarinic acetylcholine receptor (mAChR) was downregulated at the gene and protein levels in the putamen, but not in the caudate, of AUD samples. We found concordant downregulation of the M4 mAChR, specifically on dopamine D1 receptor-expressing medium spiny neurons in the rat dorsolateral striatum. Systemic administration of the selective M4 mAChR positive allosteric modulator, VU0467154, reduced home cage and operant alcohol self-administration, motivation to obtain alcohol, and cue-induced reinstatement of alcohol seeking in rats. Local microinjections of VU0467154 in the rat dorsolateral striatum reduced alcohol self-administration and cue-induced reinstatement of alcohol seeking. CONCLUSIONS: Collectively, these results identify the M4 mAChR as a potential therapeutic target for the treatment of AUD and the D1 receptor-positive medium spiny neurons in the dorsolateral striatum as a key site mediating the actions of M4 mAChR in relation to alcohol consumption and seeking.<br />
DOI: 10.1016/j.biopsych.2020.02.019 PMID: 32331824 [Indexed for MEDLINE]<br />
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[5]. Drug Alcohol Depend. 2017 Jul 1;176:154-161. doi: 10.1016/j.drugalcdep.2017.03.014. Epub 2017 May 16.<br />
Muscarinic receptor M(4) positive allosteric modulators attenuate central effects of cocaine.<br />
Dall C(1), Weikop P(1), Dencker D(1), Molander AC(1), Wörtwein G(1), Conn PJ(2), Fink-Jensen A(1), Thomsen M(3).<br />
Author information: (1)Laboratory of Neuropsychiatry, Psychiatric Centre Copenhagen and University of Copenhagen, Copenhagen, Denmark. (2)Vanderbilt Program in Drug Discovery, Vanderbilt Specialized Chemistry Center (Molecular Libraries Probe Production Centers Network; MLPCN), Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN, USA. (3)Laboratory of Neuropsychiatry, Psychiatric Centre Copenhagen and University of Copenhagen, Copenhagen, Denmark; Alcohol and Drug Abuse Research Center, McLean Hospital/Harvard Medical School, Belmont, MA, USA. Electronic address: [email protected].<br />
BACKGROUND: Cocaine addiction is a chronic brain disease affecting neurotransmission. Muscarinic cholinergic receptors modulate dopaminergic signaling in the reward system, and muscarinic receptor stimulation can block direct reinforcing effects of cocaine. Here, we tested the hypothesis that specific muscarinic M4 receptor stimulation can attenuate the discriminative stimulus effects and conditioned rewarding effects of cocaine, measures believed to predict the ability of cocaine and cocaine-associated cues to elicit relapse to drug taking. METHODS: We tested the M4-selective positive allosteric modulators VU0152100 and VU0467154 in a drug discrimination assay and a conditioned place preference assay, including extinction and reinstatement of place preference. Specificity of the cocaine discrimination effect was verified using knockout mice lacking either M1 or M4 receptors (M1-/-, M4-/-). We also replicated previous findings in cocaine-induced locomotor hyperactivity and striatal dopamine microdialysis assays. RESULTS: VU0152100 attenuated the discriminative stimulus effect of cocaine in wild-type mice and M1-/- mice, but not in M4-/- mice, without affecting rates of responding. As previously shown with VU0152100, VU0467154 almost eliminated cocaine-induced hyperactivity and striatal dopamine efflux. VU0467154 failed to attenuate acquisition of cocaine-conditioned place preference, but facilitated extinction and prevented reinstatement of the conditioned place preference. CONCLUSIONS: These findings further support the notion that M4 receptors are promising targets for the treatment of cocaine addiction, by showing that results can be replicated using distinct ligands, and that in addition to blocking reinforcing effects of cocaine relevant to ongoing drug taking, M4 positive allosteric modulators can also attenuate subjective and conditioned effects relevant to relapse.<br />
DOI: 10.1016/j.drugalcdep.2017.03.014 PMCID: PMC6423356 PMID: 28544993 [Indexed for MEDLINE]
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