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Positive allosteric modulator

Kathryn E Livingston, Jacob P Mahoney, Aashish Manglik, Roger Sunahara, John R Traynor
The intrinsic efficacy of orthosteric ligands acting at G protein-coupled receptors (GPCRs) reflects their ability to stabilize active receptor states (R*) and is a major determinant of their physiological effects. Here we present a direct way to quantify the efficacy of ligands by measuring the binding of a R*-specific biosensor to purified receptor employing interferometry. As an example, we use the mu-opioid receptor (µ-OR), a prototypic class A GPCR, and its active state sensor, nanobody-39 (Nb39). We demonstrate that ligands vary in their ability to recruit Nb39 to µ-OR and describe methadone, loperamide, and PZM21 as ligands that support unique R* conformation(s) of µ-OR...
June 22, 2018: ELife
Serhat Sezai Çiçek
GABA(A) receptors are ligand-gated ion channels consisting of five subunits from eight subfamilies, each assembled in four hydrophobic transmembrane domains. This pentameric structure not only allows different receptor binding sites, but also various types of ligands, such as orthosteric agonists and antagonists, positive and negative allosteric modulators, as well as second-order modulators and non-competitive channel blockers. A fact, that is also displayed by the variety of chemical structures found for both, synthetic as well as nature-derived GABA(A)-receptor modulators...
June 22, 2018: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
Claire Bedez, Christophe Lotz, Claire Batisse, Arnaud Vanden Broeck, Roland H Stote, Eduardo Howard, Karine Pradeau-Aubreton, Marc Ruff, Valérie Lamour
Type 2 DNA topoisomerases (Top2) are critical components of key protein complexes involved in DNA replication, chromosome condensation and segregation, as well as gene transcription. The Top2 were found to be the main targets of anticancer agents, leading to intensive efforts to understand their functional and physiological role as well as their molecular structure. Post-translational modifications have been reported to influence Top2 enzyme activities in particular those of the mammalian Top2α isoform. In this study, we identified phosphorylation, and for the first time, acetylation sites in the human Top2α isoform produced in eukaryotic expression systems...
June 18, 2018: Scientific Reports
Monika Wożniak, Paulina Cieślik, Marcin Marciniak, Tomasz Lenda, Andrzej Pilc, Joanna M Wieronska
The modified forced swim test (MFST) has excellent predictive validity for investigating the antipsychotic activity of drugs, with particular emphasis on their activity toward negative symptoms of schizophrenia. However, its face and construct validity are less understood. Therefore, in the present study, some biochemical changes within GABAergic and serotonergic neurotransmission that could be related to observed MK-801-induced disturbances and the activity of compounds active at those neurotransmitters were investigated...
June 15, 2018: Pharmacology, Biochemistry, and Behavior
Felipe Borges Almeida, Alan Rios Fonseca, Núbia Heidrich, Maurício Schüler Nin, Helena Maria Tannhauser Barros
Depression is a highly incapacitating disorder known to have a multifactorial etiology, including a hereditary genetic background. The neurosteroid allopregnanolone (ALLO) is a positive allosteric modulator of the GABAA receptor and has been shown to have an antidepressant-like effect in animals. This study aimed to assess the behavioral effect of ALLO in animals with different backgrounds of depressive-like activity. An initial population (F0) of male and female Wistar rats was screened for immobility behavior utilizing the Forced Swim Test (FST)...
June 12, 2018: Physiology & Behavior
Daniel P Radin, Yong-Xin Li, Gary Rogers, Richard Purcell, Arnold Lippa
Transmembrane AMPA receptor regulatory proteins (TARPs) govern AMPA receptor cell surface expression and distinct physiological properties including agonist affinity, desensitization and deactivation kinetics. The prototypical TARP, STG or γ2 and TARPs γ3, γ4, γ7 and γ8 are all expressed to varying degrees in the mammalian brain and differentially regulate AMPAR gating parameters. Positive allosteric AMPA receptor modulators or ampakines alter receptor rates of agonist binding/unbinding, channel opening and can offset receptor desensitization and deactivation...
June 12, 2018: Biochemical Pharmacology
Lucia Recinella, Annalisa Chiavaroli, Claudio Ferrante, Adriano Mollica, Giorgia Macedonio, Azzurra Stefanucci, Marilisa Pia Dimmito, Szabolcs Dvorácskó, Csaba Tömböly, Luigi Brunetti, Giustino Orlando, Sheila Leone
BACKGROUND: The endocannabinoid (eCB) system is strongly involved in the regulation of anxiety and feeding behavior. RVD-hemopressin(α) [RVD-hp(α)], a N-terminally extended form of hemopressin, is a negative allosteric modulator of the cannabinoid (CB) 1 receptor and a positive allosteric modulator of CB2 receptor which has been recently reported to exert anxiolytic/antidepressant and anorexigenic effects after peripheral administration in rats. Pharmacological evidences reported a possible link between brain hypocretin/orexin, monoamine and eCB systems, as regards appetite and emotional behavior control...
February 2, 2018: Pharmacological Reports: PR
Ji-Woon Kim, Kwanghoon Park, Ri Jin Kang, Edson Luck T Gonzales, Do Gyeong Kim, Hyun Ah Oh, Hana Seung, Mee Jung Ko, Kyoung Ja Kwon, Ki Chan Kim, Sung Hoon Lee, ChiHye Chung, Chan Young Shin
Autism spectrum disorder (ASD) is a neurodevelopmental disorder, featuring social communication deficit and repetitive/restricted behaviors as common symptoms. Its prevalence has continuously increased, but, till now, there are no therapeutic approaches to relieve the core symptoms, particularly social deficit. In previous studies, abnormal function of the glutamatergic neural system has been proposed as a critical mediator and therapeutic target of ASD-associated symptoms. Here, we investigated the possible roles of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs) in autism symptoms using two well-known autistic animal models, Cntnap2 knockout (KO) mice and in utero valproic acid-exposed ICR (VPA) mice...
May 22, 2018: Neuropsychopharmacology: Official Publication of the American College of Neuropsychopharmacology
Daniel P Radin, Steven Johnson, Richard Purcell, Arnold S Lippa
Neurotrophin dysregulation has been implicated in a large number of neurodegenerative and neuropsychiatric diseases. Unfortunately, neurotrophins cannot cross the blood brain barrier thus, novel means of up regulating their expression are greatly needed. It has been demonstrated previously that neurotrophins are up regulated in response to increases in brain activity. Therefore, molecules that act as cognitive enhancers may provide a clinical means of up regulating neurotrophin expression. Ampakines are a class of molecules that act as positive allosteric modulators of AMPA-type glutamate receptors...
June 6, 2018: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
Terry Kenakin, Ryan T Strachan
Seven transmembrane receptor (7TMR) responses are modulated by orthosteric and allosteric ligands to great therapeutic advantage. Here we introduce a unique class of negative allosteric modulator (NAM) - the positive allosteric modulator (PAM)-antagonist - that increases the affinity of the receptor for the agonist but concomitantly decreases agonist efficacy when cobound. Notably, the reciprocation of allosteric energy causes the orthosteric agonist to increase the affinity of the receptor for the PAM-antagonist; thus, this modulator seeks out and destroys agonist-bound receptor complexes...
June 6, 2018: Trends in Pharmacological Sciences
María Clara Gravielle
GABAA receptors mediate most of the fast inhibitory transmissions in the central nervous system. These receptors are pentameric complexes that exhibit high structural and pharmacological heterogeneity, as they can be constructed from 19 distinct subunits. GABAA receptors are the targets of numerous clinically relevant drugs used to treat various disorders such as anxiety, insomnia and epilepsy. These receptors are also the targets of many volatile anesthetics and drugs of abuse, such as alcohol. This review is focused on the effect of long-term treatment with GABA, and the positive allosteric modulators benzodiazepines, neurosteroids and ethanol on GABAA receptors...
May 31, 2018: Neurochemistry International
Mohamed Faizan Momin, Xin-Qiu Yao, Waygen Thor, Donald Hamelberg
Pin1 is a unique phosphorylation dependent peptidyl-prolyl isomerase that regulates diverse subcellular processes and an important potential therapeutic target. Functional mechanisms of Pin1 are complicated because of the two-domain structural organization: the catalytic domain both binds the specific pSer/Thr-Pro motif and catalyzes the cis/trans isomerization, whereas the WW domain can only bind the trans configuration and is speculated to be responsible for substrate binding specificity. Numerous studies of Pin1 have led to two divergent conclusions on the functional role of the WW domain...
May 31, 2018: Journal of Physical Chemistry. B
Daniel P Radin, Gary A Rogers, Kimberley E Hewitt, Richard Purcell, Arnold Lippa
BACKGROUND/AIM: Mounting evidence suggests that trophic cell signaling can be mediated by alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) activation. It has been demonstrated that exogenous application of brain-derived neurotrophic factor (BDNF) is highly neuroprotective in vitro against neurotoxic insults such as standard chemotherapies. MATERIALS AND METHODS: Because positive allosteric modulation of AMPARs with ampakines can increase both BDNF mRNA and protein in vitro and in vivo, we examined whether application of the ampakines CX614 and CX729 promoted neuroprotection against staurosporine-induced cell death in rat primary cortical neurons using propidium iodide to stain for dead cells...
June 2018: Anticancer Research
Glynis B Mattheisen, Timur Tsintsadze, Stephen M Smith
Voltage-gated sodium channels (VGSCs) are strategically positioned to mediate neuronal plasticity because of their influence on action potential waveform. VGSC function may be strongly inhibited by local anesthetic and antiepileptic drugs and modestly modulated via second messenger pathways. Here, we report that the allosteric modulators of the calcium-sensing receptor (CaSR) cinacalcet, calindol, calhex, and NPS 2143 completely inhibit VGSC current in the vast majority of cultured mouse neocortical neurons...
May 29, 2018: Cell Reports
Sami Alzarea, Shafiqur Rahman
Evidence suggests that α7 nicotinic acetylcholine receptor (α7 nAChR) in the central nervous system has a critical role in the regulation of microglial function and neuroinflammation associated with the pathophysiology of major depressive disorder (MDD). The objectives of the present study were to determine the effects of PNU 120596, an α7 nAChR positive allosteric modulator (PAM), on depressive-like behavior and expression of ionized calcium binding adaptor molecule 1 (Iba-1), a microglial marker, in male C57BL/6J mice following lipopolysaccharide (LPS) administration, an animal model for depressive-like behavior...
May 22, 2018: Progress in Neuro-psychopharmacology & Biological Psychiatry
Riley Perszyk, Brooke M Katzman, Hirofumi Kusumoto, Steven A Kell, Matthew P Epplin, Yesim A Tahirovic, Rhonda L Moore, David Menaldino, Pieter Burger, Dennis C Liotta, Stephen F Traynelis
N-methyl-d-aspartate receptors (NMDARs) are an important receptor in the brain and have been implicated in multiple neurological disorders. Many non-selective NMDAR-targeting drugs are poorly tolerated, leading to efforts to target NMDAR subtypes to improve the therapeutic index. We describe here a series of negative allosteric NMDAR modulators with submaximal inhibition at saturating concentrations. Modest changes to the chemical structure interconvert negative and positive modulation. All modulators share the ability to enhance agonist potency and are use-dependent, requiring the binding of both agonists before modulators act with high potency...
May 24, 2018: ELife
Rachel Gurrell, Pinky Dua, Gang Feng, Maria Sudworth, Mark Whitlock, David S Reynolds, Richard P Butt
The effect of PF-06372865, a subtype selective positive allosteric modulator (PAM) of the γ-aminobutyric acid type A (GABAA) receptor, on chronic low back pain was investigated in a randomised, placebo and active-controlled Phase 2 clinical trial. The parallel treatment group trial consisted of a 1 week single-blind placebo run in phase, followed by 4 weeks double-blind treatment. Patients were randomised to receive either PF-06372865, naproxen or placebo BID for 4 weeks. The primary endpoint was the numerical rating score (NRS) of low back pain intensity (LBPI) after 4 weeks of active treatment...
May 21, 2018: Pain
Matías Lasala, Jeremías Corradi, Ariana Bruzzone, María Del Carmen Esandi, Cecilia Bouzat
The cholinergic α7 nicotinic receptor gene, CHRNA7, encodes a subunit that forms the homopentameric α7 receptor, involved in learning and memory. In humans, exons 5-10 in CHRNA7 are duplicated and fused to the FAM7A genetic element, giving rise to the hybrid gene CHRFAM7A. Its product, dupα7, is a truncated subunit lacking part of the N-terminal extracellular ligand-binding domain and is associated with neurological disorders, including schizophrenia, and immunomodulation.We combined dupα7 expression on mammalian cells with patch clamp recordings to understand its functional role...
May 21, 2018: Journal of Biological Chemistry
Aram J Krauson, James G Rooney, Marcelo D Carattino
Acid-sensing ion channels (ASICs) are trimeric proton-gated cation permeable ion channels expressed primarily in neurons. Here we employed site-directed mutagenesis and electrophysiology to investigate the mechanism of inhibition of ASIC1a by diminazene. This compound inhibits mouse ASIC1a with a half-maximal inhibitory concentration (IC50) of 2.4 μM. At first, we examined whether neutralizing mutations of Glu79 and Glu416 alter diminazene block. These residues form a hexagonal array in the lower palm domain that was previously shown to contribute to pore opening in response to extracellular acidification...
2018: PloS One
J M Witkin, J L Smith, X Ping, S D Gleason, M M Poe, G Li, X Jin, J Hobbs, J M Schkeryantz, J S McDermott, A I Alatorre, J N Siemian, J W Cramer, D C Airey, K R Methuku, V V N P B Tiruveedhula, T M Jones, J Crawford, M J Krambis, J L Fisher, J M Cook, R Cerne
HZ-166 has previously been characterized as an α2,3-selective GABAA receptor modulator with anticonvulsant, anxiolytic, and anti-nociceptive properties but reduced motor effects. We discovered a series of ester bioisosteres with reduced metabolic liabilities, leading to improved efficacy as anxiolytic-like compounds in rats. In the present study, we evaluated the anticonvulsant effects KRM-II-81 across several rodent models. In some models we also evaluated key structural analogs. KRM-II-81 suppressed hyper-excitation in a network of cultured cortical neurons without affecting the basal neuronal activity...
May 3, 2018: Neuropharmacology
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