keyword
MENU ▼
Read by QxMD icon Read
search

Positive allosteric modulator

keyword
https://www.readbyqxmd.com/read/28719234/the-in-vivo-effects-of-the-cb1-positive-allosteric-modulator-gat229-on-intraocular-pressure-in-ocular-normotensive-and-hypertensive-mice
#1
Elizabeth A Cairns, Anna-Maria Szczesniak, Alex J Straiker, Pushkar M Kulkarni, Roger G Pertwee, Ganesh A Thakur, William H Baldridge, Melanie E M Kelly
PURPOSE: Orthosteric cannabinoid receptor 1 (CB1) activation leads to decreases in intraocular pressure (IOP). However, use of orthosteric CB1 agonists chronically has several disadvantages, limiting their usefulness as clinically relevant drugs. Allosteric modulators interact with topographically distinct sites to orthosteric ligands and may be useful to circumvent some of these disadvantages. The purpose of this study was to investigate the effects of the novel CB1-positive allosteric modulator (PAM) GAT229 on IOP...
July 18, 2017: Journal of Ocular Pharmacology and Therapeutics
https://www.readbyqxmd.com/read/28713569/kctd12-modulation-of-gaba-b-receptor-function
#2
Melody Li, Carol J Milligan, Haiyan Wang, Andrew Walker, Leonid Churilov, Andrew J Lawrence, Christopher A Reid, Seth C Hopkins, Steven Petrou
The molecular composition and functional diversity of native GABAB receptors (GABABR) are still poorly understood, thus hindering development of selective GABABR ligands. Potassium channel tetramerization domain-containing protein (KCTD) 12 is a GABABR auxiliary subunit and mouse KCTD12 can alter GABABR function. In this study, we sought to characterize the effects of human KCTD12 on GABABR kinetics and pharmacology, using an automated electrophysiological assay. Seizure susceptibility and ethanol consumption were also investigated in a KCTD12 knockout mouse model...
August 2017: Pharmacology Research & Perspectives
https://www.readbyqxmd.com/read/28709671/mechanism-and-properties-of-positive-allosteric-modulation-of-n-methyl-d-aspartate-receptors-by-6-alkyl-2-naphthoic-acid-derivatives
#3
Kiran Sapkota, Mark W Irvine, Guangyu Fang, Erica S Burnell, Neil Bannister, Arturas Volianskis, Georgia R Culley, Shashank M Dravid, Graham L Collingridge, David E Jane, Daniel T Monaghan
The theory that N-methyl-d-aspartate receptor (NMDAR) hypofunction is responsible for the symptoms of schizophrenia is well supported by many pharmacological and genetic studies. Accordingly, positive allosteric modulators (PAMs) that augment NMDAR signaling may be useful for treating schizophrenia. Previously we have identified several NMDAR PAMs containing a carboxylic acid attached to naphthalene, phenanthrene, or coumarin ring systems. In this study, we describe several functional and mechanistic properties of UBP684, a 2-naphthoic acid derivative, which robustly potentiates agonist responses at each of the four GluN1a/GluN2 receptors and at neuronal NMDARs...
July 11, 2017: Neuropharmacology
https://www.readbyqxmd.com/read/28707143/clinical-sleep-wake-disorders-ii-focus-on-insomnia-and-circadian-rhythm-sleep-disorders
#4
Kai Spiegelhalder, Christoph Nissen, Dieter Riemann
Insomnia and circadian rhythm sleep disorders affect large proportions of the population and have pronounced effects on quality of life and daytime performance. While the neurobiology of insomnia is not yet fully understood, circadian rhythm sleep disorders are assumed to be caused by a mismatch between the individual circadian phase position and the desired sleep-wake schedule. Benzodiazepines and non-benzodiazepine positive allosteric GABAA receptor modulators improve sleep onset and maintenance in the short-term treatment of insomnia...
July 14, 2017: Handbook of Experimental Pharmacology
https://www.readbyqxmd.com/read/28704052/discovery-and-kinetic-profiling-of-7-aryl-1-2-4-triazolo-4-3-a-pyridines-positive-allosteric-modulators-of-the-metabotropic-glutamate-receptor-2
#5
Maarten L J Doornbos, José María Cid, Jordi Haubrich, Alexandro Nunes, Jasper W van de Sande, Sophie C Vermond, Thea Mulder-Krieger, Andrés A Trabanco, Abdellah Ahnaou, Wilhelmus H Drinkenburg, Hilde Lavreysen, Laura H Heitman, Adriaan P IJzerman, Gary Tresadern
We report the synthesis and biological evaluation of a series of 7-aryl-1,2,4-triazolo[4,3-a]pyridines with mGlu2 positive allosteric modulator (PAM) activity and affinity. Besides traditional in vitro parameters of potency and affinity, kinetic parameters kon, koff and residence time (RT) were determined. The PAMs showed various kinetic profiles; kon values ranged over two orders of magnitude, whereas RT values were within a 10-fold range. Association rate constant kon was linearly correlated to affinity. Evaluation of a short, medium and long RT compound in a label-free assay indicated a correlation between RT and functional effect...
July 13, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28700952/nicotine-facilitates-nicotinic-acetylcholine-receptor-targeting-to-mitochondria-but-makes-them-less-susceptible-to-selective-ligands
#6
Kateryna Uspenska, Olena Lykhmus, Galyna Gergalova, Volodymyr Chernyshov, Hugo R Arias, Sergiy Komisarenko, Maryna Skok
Several nicotinic acetylcholine receptor (nAChR) subtypes are expressed in mitochondria to regulate the internal pathway of apoptosis in ion channel-independent manner. However, the mechanisms of nAChR activation in mitochondria and targeting to mitochondria are still unknown. Nicotine has been shown to favor nAChR pentamer assembly, folding, and maturation on the way of biosynthesis. The idea of the present work was to determine whether nicotine affects the content, glycosylation, and function of mitochondrial nAChRs...
July 9, 2017: Neuroscience Letters
https://www.readbyqxmd.com/read/28694498/analysis-of-positive-and-negative-allosteric-modulation-in-metabotropic-glutamate-receptors-4-and-5-with-a-dual-ligand
#7
James A R Dalton, Jean-Philippe Pin, Jesús Giraldo
As class C GPCRs and regulators of synaptic activity, human metabotropic glutamate receptors (mGluRs) 4 and 5 are prime targets for allosteric modulation, with mGlu5 inhibition or mGlu4 stimulation potentially treating conditions like chronic pain and Parkinson's disease. As an allosteric modulator that can bind both receptors, 2-Methyl-6-(phenylethynyl)pyridine (MPEP) is able to negatively modulate mGlu5 or positively modulate mGlu4. At a structural level, how it elicits these responses and how mGluRs undergo activation is unclear...
July 10, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28685026/cholecystokinin-induced-satiety-a-key-gut-servomechanism-that-is-affected-by-the-membrane-microenvironment-of-this-receptor
#8
REVIEW
A J Desai, M Dong, K G Harikumar, L J Miller
The gastrointestinal (GI) tract has a central role in nutritional homeostasis, as location for food ingestion, digestion and absorption, with the gut endocrine system responding to and regulating these events, as well as influencing appetite. One key GI hormone with the full spectrum of these activities is cholecystokinin (CCK), a peptide released from neuroendocrine I cells scattered through the proximal intestine in response to fat and protein, with effects to stimulate gall bladder contraction and pancreatic exocrine secretion, to regulate gastric emptying and intestinal transit, and to induce satiety...
December 2016: International Journal of Obesity Supplements
https://www.readbyqxmd.com/read/28684359/significance-of-the-nicotinic-alpha7-receptor-in-cognition-and-antipsychotic-like-behavior-in-the-rat
#9
Marie-Louise G Wadenberg, Dina Manetti, Maria Novella Romanelli, Hugo R Arias
Schizophrenic (SCH) patients show cognitive impairment in attentional performance. Positive allosteric modulators (PAMs) of α7 nicotinic acetylcholine receptors (nAChRs) such as the Alzheimer's drug galantamine (GAL) and PAM-2 are documented to have pro-cognitive properties. However, it is not well established if these properties would be lost, or may hamper antipsychotic efficacy, when given as an adjunct to an antipsychotic which is needed for managing psychotic symptoms. Using adult male Wistar rats, we here investigated the effects of: a) GAL, alone or co-administered with the antipsychotic risperidone (RISP), on acute phencyclidine (PCP)-induced deficits in the attentional set-shifting (ASST) test; b) PAM-2, alone and co-administered with RISP, in the conditioned avoidance response (CAR) test for antipsychotic activity...
July 3, 2017: Behavioural Brain Research
https://www.readbyqxmd.com/read/28680877/metabolic-products-of-linalool-and-modulation-of-gabaa-receptors
#10
Sinem Milanos, Shaimaa A Elsharif, Dieter Janzen, Andrea Buettner, Carmen Villmann
Terpenoids are major subcomponents in aroma substances which harbor sedative physiological potential. We have demonstrated that various monoterpenoids such as the acyclic linalool enhance GABAergic currents in an allosteric manner in vitro upon overexpression of inhibitory α1β2 GABAA receptors in various expression systems. However, in plants or humans, i.e., following intake via inhalation or ingestion, linalool undergoes metabolic modifications including oxygenation and acetylation, which may affect the modulatory efficacy of the generated linalool derivatives...
2017: Frontiers in Chemistry
https://www.readbyqxmd.com/read/28679508/a-system-independent-scale-%C3%AE-log-max-ec50-of-agonism-and-allosteric-modulation-for-assessment-of-selectivity-bias-and-receptor-mutation
#11
Terry P Kenakin
An index of agonism is described which can be used to quantify agonist receptor selectivity, bias, cell-based agonism and the effects of receptor mutation on signaling . The parameter is derived from agonist concentration-response curves and is comprised of the maximal response to the agonist (max) and the EC50 (concentration of agonist producing half maximal response) in the form of ΔLog(max/EC50). This parameter is derived from equations describing agonists as positive allosteric facilitators of receptor-signaling protein interaction...
July 5, 2017: Molecular Pharmacology
https://www.readbyqxmd.com/read/28679049/role-of-mglu5-receptors-and-inhibitory-neurotransmission-in-m1-dependent-muscarinic-ltd-in-the-prefrontal-cortex-implications-in-schizophrenia
#12
Ayan Ghoshal, Sean P Moran, Jonathan W Dickerson, Max E Joffe, Brad A Grueter, Zixiu Xiang, Craig W Lindsley, Jerri M Rook, P Jeffrey Conn
Selective potentiation of the mGlu5 subtype of metabotropic glutamate (mGlu) receptor using positive allosteric modulators (PAMs) has robust cognition-enhancing effects in rodent models that are relevant for schizophrenia. Until recently, these effects were thought to be due to potentiation of mGlu5-induced modulation of NMDA receptor (NMDAR) currents and NMDAR-dependent synaptic plasticity. However, "biased" mGlu5 PAMs that do not potentiate mGlu5 effects on NMDAR currents show efficacy that is similar to that of prototypical mGlu5 PAMs, suggesting that NMDAR-independent mechanisms must be involved in these actions...
July 5, 2017: ACS Chemical Neuroscience
https://www.readbyqxmd.com/read/28669783/gabaergic-signaling-within-the-basolateral-amygdala-complex-modulates-resistance-to-the-labilization-reconsolidation-process
#13
Pablo Javier Espejo, Pharm D Vanesa Ortiz, Irene Delia Martijena, Victor Alejandro Molina
It is well known that stress can affect mnemonic processes. In particular, stress before contextual fear conditioning induces a memory which exhibits resistance to being interfered with by Midazolam (MDZ) when applied after memory retrieval. Moreover, stress exposure strongly affects GABAergic transmission within the Basolateral Amygdala Complex (BLA), a brain structure critically involved in fear memory processing. The present study evaluated the involvement of GABAergic signaling within the BLA on the induction of resistance to memory reconsolidation interference...
June 29, 2017: Neurobiology of Learning and Memory
https://www.readbyqxmd.com/read/28657424/heroin-piracetam-mixture-suggested-mechanisms-of-action-and-risks-of-misinterpretation-for-drug-users
#14
Simone Cappelletti, Francesco Lombardo, Pasquale Vitale, Giuseppe Vallone, Costantino Ciallella
Piracetam is a positive allosteric modulator of the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor that has been frequently used in the treatment of cognitive disorders. Press and internet reports indicate that the use of piracetam, as a heroin adulterant, has spread rapidly in some countries, especially in Asia and Europe. Its use, as adulterant, is believed to produce more profound desirable effects, while decreasing hangover. Recent surveys demonstrated that piracetam protects neurons from heroin-induced apoptosis...
January 1, 2017: Medico-legal Journal
https://www.readbyqxmd.com/read/28646511/control-of-autoimmune-inflammation-using-liposomes-to-deliver-positive-allosteric-modulators-of-metabotropic-glutamate-receptors
#15
Joshua M Gammon, Arjun R Adapa, Christopher M Jewell
Multiple sclerosis (MS) is an autoimmune disease where myelin is incorrectly recognized as foreign and attacked by the adaptive immune system. Dendritic cells (DCs) direct adaptive immunity by presenting antigens to T cells, therefore serving as a target for autoimmune therapies. N-Phenyl-7-(hydroxyimino)cyclopropa[b]chromen-1a-carboxamide (PHCCC), a positive allosteric modulator of metabotropic glutamate receptor 4 (mGluR4), can promote regulatory T cells by altering cytokine secretion to bias T cell differentiation...
June 24, 2017: Journal of Biomedical Materials Research. Part A
https://www.readbyqxmd.com/read/28642232/a-single-amino-acid-residue-at-transmembrane-domain-4-of-the-alpha-subunit-influences-carisoprodol-direct-gating-efficacy-at-gabaa-receptors
#16
Manoj Kumar, Manish Kumar, John Freund, Glenn H Dillon
The muscle relaxant carisoprodol (CSP, trade name Soma) has recently been controlled at the federal level as a Schedule IV drug due to its high abuse potential and consequences of misuse, such as withdrawal syndrome, delusions, seizures and even death. Recent work has shown that carisoprodol can directly gate and allosterically modulate the GABAA receptor. These actions are subunit-dependent; compared to other GABAA receptors, carisoprodol has nominal direct gating effects in α3β2γ2receptors. Here, using site-directed-mutagenesis and whole cell patch clamp electrophysiology in transiently transfected HEK293 cells, we examined the role of GABAA receptor α subunit transmembrane domain 4 (TM4) amino acids in direct gating and allosteric modulatory actions of carisoprodol...
June 22, 2017: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/28640864/targeting-breast-cancer-cells-by-mrs1477-a-positive-allosteric-modulator-of-trpv1-channels
#17
Mustafa Nazıroğlu, Bilal Çiğ, Walter Blum, Csaba Vizler, Andrea Buhala, Annamária Marton, Róbert Katona, Katalin Jósvay, Beat Schwaller, Zoltán Oláh, László Pecze
There is convincing epidemiological and experimental evidence that capsaicin, a potent natural transient receptor potential cation channel vanilloid member 1 (TRPV1) agonist, has anticancer activity. However, capsaicin cannot be given systemically in large doses, because of its induction of acute pain and neurological inflammation. MRS1477, a dihydropyridine derivative acts as a positive allosteric modulator of TRPV1, if added together with capsaicin, but is ineffective, if given alone. Addition of MRS1477 evoked Ca2+ signals in MCF7 breast cancer cells, but not in primary breast epithelial cells...
2017: PloS One
https://www.readbyqxmd.com/read/28630250/amplification-of-mglu5-endocannabinoid-signaling-rescues-behavioral-and-synaptic-deficits-in-a-mouse-model-of-adolescent-and-adult-dietary-polyunsaturated-fatty-acids-imbalance
#18
Antonia Manduca, Anissa Bara, Thomas Larrieu, Olivier Lassalle, Corinne Joffre, Sophie Layé, Olivier J Manzoni
Energy-dense, yet nutritionally-poor food is a high-risk factor for mental health disorders. This is of particular concern during adolescence, a period often associated with increased consumption of low nutritional content food and higher prevalence of mental health disorders. Indeed, there is an urgent need to understand the mechanisms linking unhealthy diet and mental disorders. Deficiency in n-3 polyunsaturated fatty acid (PUFAs) is a hallmark of poor nutrition and mood disorders. Here, we developed a mouse model of n-3 PUFAs deficiency lasting from adolescence into adulthood...
June 19, 2017: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
https://www.readbyqxmd.com/read/28619476/brexanolone-sage-547-injection-in-post-partum-depression-a-randomised-controlled-trial
#19
Stephen Kanes, Helen Colquhoun, Handan Gunduz-Bruce, Shane Raines, Ryan Arnold, Amy Schacterle, James Doherty, C Neill Epperson, Kristina M Deligiannidis, Robert Riesenberg, Ethan Hoffmann, David Rubinow, Jeffrey Jonas, Steven Paul, Samantha Meltzer-Brody
BACKGROUND: Post-partum depression is a serious mood disorder in women that might be triggered by peripartum fluctuations in reproductive hormones. This phase 2 study investigated brexanolone (USAN; formerly SAGE-547 injection), an intravenous formulation of allopregnanolone, a positive allosteric modulator of γ-aminobutyric acid (GABAA) receptors, for the treatment of post-partum depression. METHODS: For this double-blind, randomised, placebo-controlled trial, we enrolled self-referred or physician-referred female inpatients (≤6 months post partum) with severe post-partum depression (Hamilton Rating Scale for Depression [HAM-D] total score ≥26) in four hospitals in the USA...
June 12, 2017: Lancet
https://www.readbyqxmd.com/read/28619258/rho-kinase-dependent-desensitization-of-gpr39-a-unique-mechanism-of-gpcr-downregulation
#20
Yuji Shimizu, Ryokichi Koyama, Tomohiro Kawamoto
GPR39, a G-protein-coupled receptor activated by zinc, reportedly activates multiple intracellular signaling pathways via Gs, Gq, G12/13, and β-arrestin, but little is known about downregulation of the receptor upon its activation. To our knowledge, this is the first report on the mechanism of feedback regulation of GPR39 function determined in GPR39-expressing HEK293 cells (HEK293-GPR39) as a model cell system. In HEK293-GPR39 cells, GPR39-C3, which is a positive allosteric modulator, activated cAMP production (downstream of Gs), IP1 accumulation (downstream of Gq), SRF-RE-dependent transcription (downstream of G12/13), and β-arrestin recruitment...
June 12, 2017: Biochemical Pharmacology
keyword
keyword
94230
1
2
Fetch more papers »
Fetching more papers... Fetching...
Read by QxMD. Sign in or create an account to discover new knowledge that matter to you.
Remove bar
Read by QxMD icon Read
×

Search Tips

Use Boolean operators: AND/OR

diabetic AND foot
diabetes OR diabetic

Exclude a word using the 'minus' sign

Virchow -triad

Use Parentheses

water AND (cup OR glass)

Add an asterisk (*) at end of a word to include word stems

Neuro* will search for Neurology, Neuroscientist, Neurological, and so on

Use quotes to search for an exact phrase

"primary prevention of cancer"
(heart or cardiac or cardio*) AND arrest -"American Heart Association"