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ACS Chemical Neuroscience

Wing-Yu Fu, Xiujiao Wang, Nancy Y Ip
Alzheimer's disease is a progressive neurodegenerative disease, and its incidence is expected to increase owing to the aging population worldwide. Current therapies merely provide symptomatic relief. Therefore, interventions for AD that delay the disease onset or progression are urgently required. Recent genomics and functional studies suggest that immune/inflammatory pathways are involved in the pathogenesis of AD. Although many anti-inflammatory drug candidates have undergone clinical trials, most have failed...
September 17, 2018: ACS Chemical Neuroscience
José María Cid, Hilde Lavreysen, Gary Tresadern, Laura Pérez-Benito, Fulgencio Tovar, Alberto Fontana, Andrés A Trabanco
The metabotropic glutamate 7 (mGlu7) receptor belongs to the group III of mGlu receptors. Since the mGlu7 receptor can control excitatory neurotransmission in the hippocampus and cortex, modulation of the receptor may has therapeutic benefit in several CNS diseases. However, mGlu7 remains relatively unexplored amongst the eight known mGlu receptors partly because of the limited availability of tool compounds to interrogate its potential therapeutic utility. Here we report the discovery of a new class of mGlu7 allosteric agonists...
September 14, 2018: ACS Chemical Neuroscience
Michael Wasko, Paula A Witt-Enderby, Christopher K Surratt
The West African iboga plant has been used for centuries by the Bwiti and Mbiri tribes to induce hallucinations during religious ceremonies. Ibogaine, the principal alkaloid responsible for iboga's psychedelic properties, was isolated and sold as an antidepressant in France for decades before its adverse effects precipitated its removal from the market. An ibogaine resurgence in the 1960s was driven by U.S. heroin addicts who claimed that ibogaine cured their opiate addictions. Behavioral pharmacologic studies in animal models provided evidence that ibogaine could blunt self-administration of not only opiates but cocaine, amphetamines, and nicotine...
September 14, 2018: ACS Chemical Neuroscience
Yajuan Qin, Luofan Ni, Jiawei Shi, Zhiying Zhu, Saijian Shi, Ai-Leen Lam, Julia Magiera, Sunderajhan Sekar, Andy Kuo, Maree T Smith, Tingyou Li
A series of fentanyl analogues modified at the phenyl group of the phenethyl with alkyl and/or hydroxyl and alkoxy, and the phenyl group in the anilido moiety replaced with benzyl or substituted benzyl, were synthesized. The in vitro opioid receptor functional activity of these compounds was evaluated by assessment of their ability to modulate forskolin-stimulated cAMP accumulation and by their ability to induce β-arrestin2 recruitment. Compound 12 is a potent μ-opioid (MOP) receptor agonist, a potent κ-opioid (KOP) receptor antagonist with weak β-arrestin2 recruitment activity...
September 14, 2018: ACS Chemical Neuroscience
Wei Jing, Yifan Zhang, Qing Cai, Guoqiang Chen, Lin Wang, Xiaoping Yang, Weihong Zhong
The strategy of using electrical stimulation (ES) to promote neural differentiation and regeneration of injured nerves is proven feasible. The study on the possible molecular mechanisms in relation to this ES promotion effect should be helpful to understand the phenomenon. In this study, it was identified the neuronal differentiation of PC12 cells was enhanced when the electric field intensity was in the range of 30-80 mV/mm, lower or higher electric field intensity displayed inferior effect. Under ES, however, levels of intracellular reactive oxygen species (ROS), intracellular Ca2+ dynamics and expression of TREK-1 were measured gradually increasing alongside higher electric field intensity...
September 13, 2018: ACS Chemical Neuroscience
Michael Stephen Placzek, Frederick A Schroeder, Tao Che, Hsiao-Ying Wey, Ramesh Neelamegam, Changning Wang, Bryan L Roth, Jacob M Hooker
Kappa opioid receptor (KOR) modulation has been pursued in many conceptual frameworks for the treatment of human pain, depression and anxiety. As such, several imaging tools have been developed to characterize the density of KORs in the human brain and its occupancy by exogenous drug-like compounds. While exploring the pharmacology of KOR tool compounds using positron emission tomography (PET), we observed discrepancies in the apparent competition binding as measured by changes in binding potential (BPND )...
September 13, 2018: ACS Chemical Neuroscience
Krystian A Kozek, Yu Du, Swagat Sharma, Francis J Prael, Brittany D Spitznagel, Sujay V Kharade, Jerod S Denton, Corey R Hopkins, C David Weaver
G protein-gated, inwardly rectifying, potassium (GIRK) channels are important regulators of cellular excitability throughout the body. GIRK channels are heterotetrameric and homotetrameric combinations of the Kir 3.1-4 (GIRK1-4) subunits. Different subunit combinations are expressed throughout the central nervous system (CNS) and the periphery, and most of these combinations contain a GIRK1 subunit. For example, the predominance of GIRK channels in the CNS are composed of GIRK1 and GIRK2 subunits, while the GIRK channels in cardiac atrial myocytes are made up mostly of GIRK1 and GIRK4 subunits...
September 13, 2018: ACS Chemical Neuroscience
Gary Tin, Tarek Mohamed, Arash Shakeri, Amy Trinh Pham, Praveen P N Rao
Treating Alzheimer's disease (AD) is a major challenge at the moment with no new drugs available to cure this devastating neurodegenerative disorder. In this regard, drug repurposing, which aims to determine novel therapeutic usage for drugs already approved by the regulatory agencies, is a pragmatic approach to discover novel treatment strategies. Selective serotonin reuptake inhibitors (SSRIs) are a known class of United States Food and Drug Administration approved drugs used in the treatment of depression...
September 11, 2018: ACS Chemical Neuroscience
Anita H Lewin, Larry Brieaddy, Jeffrey R Deschamps, Gregory H Imler, S Wayne Mascarella, P Anantha Reddy, F Ivy Carroll
The demonstrated role of PKCβ in  mediating amphetamine-stimulated dopamine efflux, which regulates amphetamine-induced dopamine transporter trafficking and activity, has promoted the research use of the selective, reversible PKCβ inhibitor (9 S)-9-[(dimethylamino)methyl]-6,7,10,11-tetrahydro-9 H,18 H-5,21:12,17-dimethenodibenzo[ e,k]pyrrolo[3,4- h][1,4,13]oxadiazacyclohexadecine-18,20(19 H)-dione, ruboxistaurin. Despite the interest in development of ruboxistaurin as the mesylate monohydrate (Arxxant) for the treatment of diabetic retinopathy, macular edema, and nephoropathy, several crucial details in physicochemical characterization were erroneous or missing...
September 11, 2018: ACS Chemical Neuroscience
Lucas B Thal, Ian D Tomlinson, Meagan A Quinlan, Oleg Kovtun, Randy D Blakely, Sandra J Rosenthal
The dopamine transporter (DAT) is a transmembrane protein that terminates dopamine signaling in the brain by driving rapid dopamine reuptake into presynaptic nerve terminals. Several lines of evidence indicate that DAT dysfunction is linked to neuropsychiatric disorders such as attention-deficit/hyperactivity disorder (ADHD), bipolar disorder (BPD), and autism spectrum disorder (ASD). Indeed, individuals with these disorders have been found to express the rare, functional DAT coding variant Val559, which confers anomalous dopamine efflux (ADE) in vitro and in vivo...
September 11, 2018: ACS Chemical Neuroscience
Thomas Jack, Michele Leuenberger, Marc-David Ruepp, Sanjeev Kumar V Vernekar, Andrew J Thompson, Sophie Braga-Lagache, Manfred Heller, Martin Lochner
The serotonin-gated 5-HT3 receptor is a ligand-gated ion channel. Its location at the synapse in the central and peripheral nervous system has rendered it a prime pharmacological target, for example, for antiemetic drugs that bind with high affinity to the neurotransmitter binding site and prevent the opening of the channel. Advances in structural biology techniques have led to a surge of disclosed three-dimensional receptor structures; however, solving ligand-bound high-resolution 5-HT3 receptor structures has not been achieved to date...
September 11, 2018: ACS Chemical Neuroscience
Matthew J O'Connor, Lindsey L Beebe, Davide Deodato, Rebecca E Ball, A Tyler Page, Ariel J VanLeuven, Kyle T Harris, Sungdae Park, Vani Hariharan, James D Lauderdale, Timothy M Dore
γ-Amino butyric acid (GABA) mediated signaling is critical in the central and enteric nervous systems, pancreas, lungs and other tissues. It is associated with many neurological disorders and craniofacial development. Glutamic acid decarboxylase (GAD) synthesizes GABA from glutamate, and knockdown of the gad1 gene results in craniofacial defects that are lethal in zebrafish. To bypass this and enable observation of the neurological defects resulting from knocking down gad1 expression, a photoactivatable morpholino oligonucleotide (MO) against gad1 was prepared by cyclization with a photocleavable linker rendering the MO inactive...
September 10, 2018: ACS Chemical Neuroscience
Jiyue Zheng, Xiaohu Zhang, Xuechu Zhen
Parkinson's disease (PD) is a neurodegenerative disease with significant unmet medical needs. The current dopamine-centered treatments aim to restore motor functions of patients without slowing the disease progression. Long-term usage of these drugs is associated with diminished efficacy, motor fluctuation, and dyskinesia. Furthermore, the non-motor features associated with PD such as sleep disorder, pain and psychiatric symptoms are poorly addressed by the dopaminergic treatments. Adenosine receptor A2A antagonists have emerged as potential treatment for PD in the past decade...
September 10, 2018: ACS Chemical Neuroscience
Michael R Kilbourn, Robert A Koeppe
Positron emission tomography (PET) studies of the monoamine neurotransmitter systems in the human brain employ a variety of radiotracers targeting the many receptors, transporters, and enzymes present in monoaminergic neurons. One of these is the vesicular monoamine transporter 2 (VMAT2), the protein responsible for the energy-dependent accumulation of monoamines into synaptic vesicles. The development of in vivo imaging radiotracers for VMAT2 is a story of starting with a well-characterized clinically used drug (tetrabenazine) which had a pharmacologically active metabolite: that metabolite that was in stepwise fashion refined and modified to provide both carbon-11 and fluorine-18 labeled VMAT2 radiotracers that are now used for human PET studies of neurodegenerative and psychiatric diseases...
September 10, 2018: ACS Chemical Neuroscience
Lucile Estrade, Jean-Christophe Cassel, Sandrine Parrot, Patricia Duchamp-Viret, Barbara Ferry
Previous work has shown that β-adrenergic and GABAergic systems in the basolateral amygdala (BLA) are involved in the acquisition of conditioned odor aversion (COA) learning. The involvement of α2 -adrenoreceptors, however, is poorly documented. In a first experiment, male Long-Evans rats received infusions of 0.1 μg of the selective α2 -antagonist dexefaroxan (Dex) in the BLA before being exposed to COA learning. In a second experiment, levels of norepinephrine (NE) were analyzed following Dex retrodialysis into the BLA...
September 10, 2018: ACS Chemical Neuroscience
Ayaz Anwar, Ruqaiyyah Siddiqui, Naveed Ahmed Khan
Pathogenic free-living amoebae including Acanthamoeba spp., Balamuthia mandrillaris, and Naegleria fowleri cause infections of the central nervous system (CNS), which almost always prove fatal. The mortality rate is high with the CNS infections caused by these microbes despite modern developments in healthcare and antimicrobial chemotherapy. The low awareness, delayed diagnosis, and lack of effective drugs are major hurdles to overcome these challenges. Nanomaterials have emerged as vital tools for concurrent diagnosis and therapy, which are commonly referred to as theranostics...
September 10, 2018: ACS Chemical Neuroscience
Sandra Aurora Niño, Adriana Morales-Martínez, Erika Chi-Ahumada, Leticia Carrizales, Roberto Salgado-Delgado, Francisca Pérez-Severiano, Sofía Díaz-Cintra, María E Jiménez-Capdeville, Sergio Zarazúa
Worldwide, every year there is an increase in the number of people exposed to inorganic arsenic (iAs) via drinking water. Human populations present impaired cognitive function as a result of prenatal and childhood iAs exposure, while studies in animal models demonstrate neurobehavioral deficits accompanied by neurotransmitter, protein, and enzyme alterations. Similar impairments have been observed in close association with Alzheimer's disease (AD). In order to determine whether iAs promotes the pathophysiological progress of AD, we used the 3xTgAD mouse model...
September 10, 2018: ACS Chemical Neuroscience
Samuel Obeng, Huiqun Wang, Abdulmajeed Jali, David L Stevens, Hamid I Akbarali, William L Dewey, Dana E Selley, Yan Zhang
Structure-activity relationship (SAR) studies of numerous opioid ligands have shown that introduction of a methyl or ethyl group on the tertiary amino group at position 17 of the epoxymorphinan skeleton generally results in a mu opioid receptor (MOR) agonist while introduction of a cyclopropylmethyl group typically leads to an antagonist. Furthermore, it has been shown that introduction of heterocyclic ring systems at position 6 can favor antagonism. However, it was reported that 17-cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6β-[(2'-indolyl)acetamido]morphinan (INTA), which bears a cyclopropylmethyl group at position 17 and an indole ring at position 6, acted as a MOR agonist...
September 7, 2018: ACS Chemical Neuroscience
Thuy Nguyen, Thomas F Gamage, Ann M Decker, Nadezhda German, Tiffany L Langston, Charlotte E Farquhar, Terry P Kenakin, Jenny L Wiley, Brian F Thomas, Yanan Zhang
Allosteric modulators have attracted significant interest as an alternate strategy to modulate CB1 receptor signaling for therapeutic benefits that may avoid the adverse effects associated with orthosteric ligands. Here we extended our previous structure-activity relationship studies on the diarylurea-based CB1 negative allosteric modulators (NAMs) by introducing five-membered heterocycles to replace the 5-pyrrolidinylpyridinyl group in PSNCBAM-1 (1), one of the first generation CB1 allosteric modulators. Many of these compounds had comparable potency to 1 in blocking the CB1 agonist CP55,940 stimulated calcium mobilization and [35S]GTP-γ-S binding...
September 6, 2018: ACS Chemical Neuroscience
Yi Xi He, Zhong Wang Yu, Sheng-Di Chen
Parkinson's disease is pathologically characterized by the degeneration of dopaminergic neurons in the substantia nigra and the accumulation of neuronal cytoplasmic inclusions known as Lewy bodies, which are primarily composed of α-synuclein. Post-translational modifications of α-synuclein induced by nitrative stress have been linked to neurodegeneration. Here, we review the concept of α-synuclein nitration and its biological consequences. We also discuss the pathological roles of nitrated α-synuclein and their potential clinical implications in Parkinson's disease...
September 5, 2018: ACS Chemical Neuroscience
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