Search results for "partial agonist"

Subchronic vortioxetine treatment -but not escitalopram- enhances pyramidal neuron activity in the rat prefrontal cortex.

2017

Abstract Vortioxetine (VOR) is a multimodal antidepressant drug. VOR is a 5-HT 3 -R, 5-HT 7 -R and 5-HT 1D -R antagonist, 5-HT 1B -R partial agonist, 5-HT 1A -R agonist, and serotonin transporter (SERT) inhibitor. VOR shows pro-cognitive activity in animal models and beneficial effects on cognitive dysfunction in major depressive patients. Here we compared the effects of 14-day treatments with VOR and escitalopram (ESC, selective serotonin reuptake inhibitor) on neuronal activity in the medial prefrontal cortex (mPFC). Ten groups of rats (5 standard, 5 depleted of 5-HT with p -chlorophenylalanine -pCPA-, used as model of cognitive impairment) were fed with control food or with two doses of …

Moving Towards Precision Urologic Oncology: Targeting Enzalutamide-resistant Prostate Cancer and Mutated Forms of the Androgen Receptor Using the Nov…

2017

Abstract Darolutamide (ODM-201) is a novel androgen receptor (AR) antagonist with a chemical structure distinctly different from currently approved AR antagonists that targets both wild-type and mutated ligand binding domain variants to inhibit AR nuclear translocation. Here, we evaluate the activity of darolutamide in enzalutamide-resistant castration resistant prostate cancer (CRPC) as well as in AR mutants detected in patients after treatment with enzalutamide, abiraterone, or bicalutamide. Darolutamide significantly inhibited cell growth and AR transcriptional activity in enzalutamide-resistant MR49F cells in vitro, and led to decreased tumor volume and serum prostate-specific antigen l…

Why use long acting bronchodilators in chronic obstructive lung diseases? An extensive review on formoterol and salmeterol

2015

Abstract Long-acting β 2 -adrenoceptor agonists, formoterol and salmeterol, represent a milestone in the treatments of chronic obstructive lung diseases. Although no specific indications concerning the choice of one molecule rather than another are provided by asthma and COPD guidelines, they present different pharmacological properties resulting in distinct clinical employment possibilities. In particular, salmeterol has a low intrinsic efficacy working as a partial receptor agonist, while formoterol is a full agonist with high intrinsic efficacy. From a clinical perspective, in the presence of low β 2 -adrenoceptors availability, like in inflamed airways, a full agonist can maintain its b…

The In Vitro Pharmacological Profile Of LAS100977 - A Potent, Selective And Long-acting Beta-2 Receptor Agonist

2010

Coupling between agonist and chloride ionophore sites of the GABA(A) receptor: agonist/antagonist efficacy of 4-PIOL.

2000

Eight gamma-aminobutyric acid (GABA) mimetics were tested on their ability to differentiate native GABA(A) receptor subtypes present in various rat brain regions. In rat brain cryostat sections, little regional variations by the agonistic actions of muscimol, thiomuscimol, 4,5,6,7-tetrahydroisoazolo(5,4-c)pyridin-3-ol, piperidine-4-sulphonic acid, taurine and beta-alanine on [35S]t-butylbicyclophosphorothionate ([35S]TBPS) binding to GABA(A) receptor channels were found. They were very similar to those found for GABA itself and indicated no direct correlation with single subunit distributions for any of these compounds. Only the low-efficacy GABA mimetic 5-(4-piperidyl)isoxazol-3-ol (4-PIOL…

Exploring kainate receptor pharmacology using molecular dynamics simulations.

2010

Ionotropic glutamate receptors (iGluRs) are enticing targets for pharmaceutical research; however, the search for selective ligands is a laborious experimental process. Here we introduce a purely computational procedure as an approach to evaluate ligand–iGluR pharmacology. The ligands are docked into the closed ligand-binding domain and during the molecular dynamics (MD) simulation the bi-lobed interface either opens (partial agonist/antagonist) or stays closed (agonist) according to the properties of the ligand. The procedure is tested with closely related set of analogs of the marine toxin dysiherbaine bound to GluK1 kainate receptor. The modeling is set against the abundant binding data …

Structural Mechanism of N-Methyl-D-Aspartate Receptor Type 1 Partial Agonism

2012

N-methyl-D-aspartate (NMDA) receptors belong to a family of ionotropic glutamate receptors that contribute to the signal transmission in the central nervous system. NMDA receptors are heterotetramers that usually consist of two GluN1 and GluN2 monomers. The extracellular ligand-binding domain (LBD) of a monomer is comprised of discontinuous segments that form the functional domains D1 and D2. While the binding of a full agonist glycine to LBD of GluN1 is linked to cleft closure and subsequent ion-channel opening, partial agonists are known to activate the receptor only sub-maximally. Although the crystal structures of the LBD of related GluA2 receptor explain the mechanism for the partial a…

Research on Acute Toxicity and the Behavioral Effects of Methanolic Extract from Psilocybin Mushrooms and Psilocin in Mice

2015

The pharmacological activities and acute toxicity of the psilocin (PC) and dried residues of the crude extracts of psychotropic mushrooms were investigated in mice. The hallucinogenic substances were effectively isolated, by using methanol, from the species of Psilocybe semilanceata and Pholiotina cyanopus, that were collected in the north-east region of Poland. The chemical analysis of these extracts, which was performed by liquid chromatography with mass spectrometry detection (LC-MS), indicated the presence of psilocin and other hallucinogenic substances, including indolealkylamines and their phosphorylated analogues. When the pure psilocin or fungal extracts were used, slight difference…

Full and Partial Agonism of Ionotropic Glutamate Receptors Indicated by Molecular Dynamics Simulations

2011

Ionotropic glutamate receptors (iGluRs) are synaptic proteins that facilitate signal transmission in the central nervous system. Extracellular iGluR cleft closure is linked to receptor activation; however, the mechanism underlying partial agonism is not entirely understood. Full agonists close the bilobed ligand-binding domain (LBD), while antagonists prevent closure; the transmembrane ion channel either opens or stays closed, respectively. Although some bulky partial agonists produce intermediate iGluR-LBD closure, the available crystal structures also imply that the cleft can be shut with certain partial agonists. Recently, we have shown that the iGluR-LBD closure stage can be recreated b…

Therapeutic Monitoring of Aripiprazole by HPLC with Column-Switching and Spectrophotometric Detection

2005

Aripiprazole is a novel atypical antipsychotic drug for the treatment of schizophrenia and schizoaffective disorders (1)(2)(3). The drug is metabolized by the cytochrome P450 isoenzymes 3A4 and 2D6 (4). Because of high interindividual variability in the expression of these enzymes, the aripiprazole concentration varies among healthy individuals after administration of the drug (5). In patients, insufficient response or side effects, such as somnolence, akathisia, or nausea, may result from too low or too high drug concentrations. Therapeutic drug monitoring (TDM), which is established practice for many antipsychotic drugs (6)(7), may be helpful for patients treated with aripiprazole. We mea…