A5066208624- Receptor Mechanisms and Signaling
- Neuropeptides and Animal Physiology
- Pharmacological Effects and Assays
- Adipose Tissue and Metabolism
- Neuroscience and Neuropharmacology Research
- Cancer, Stress, Anesthesia, and Immune Response
- Mast cells and histamine
- Adenosine and Purinergic Signaling
- Protein Kinase Regulation and GTPase Signaling
- Ion channel regulation and function
- Mass Spectrometry Techniques and Applications
- Heart Failure Treatment and Management
- Computational Drug Discovery Methods
- Stress Responses and Cortisol
- Eicosanoids and Hypertension Pharmacology
- Microbial Inactivation Methods
- Toxin Mechanisms and Immunotoxins
- Heart Rate Variability and Autonomic Control
- Bacteriophages and microbial interactions
- Cardiac electrophysiology and arrhythmias
- Pharmacological Receptor Mechanisms and Effects
- Polyamine Metabolism and Applications
- Coagulation, Bradykinin, Polyphosphates, and Angioedema
- Obesity, Physical Activity, Diet
- Birth, Development, and Health
Queen's Medical Centre
2014-2024
University of Nottingham
2015-2024
Nottingham University Hospitals NHS Trust
2023-2024
King's College London
2024
Lonza (United States)
2023
St. Michael's Hospital
2022
Unity Health Toronto
2022
University of Maryland, Baltimore
2022
University of Saskatchewan
2021
Towson University
2018-2020
Background and purpose: There are two important properties of receptor–ligand interactions: affinity (the ability the ligand to bind receptor) efficacy complex induce a response). Ligands classified as agonists or antagonists depending on whether not they have efficacy. In theory, it is possible develop selective based affinity, intrinsic both. This study examined 31 β‐adrenoceptor at three human β‐adrenoceptors determine current subtype because Experimental approach: Stable clonal CHO‐K1...
Beta-adrenoceptor antagonists ("beta-blockers") are one of the most widely used classes drugs in cardiovascular medicine (hypertension, ischaemic heart disease and increasingly failure) as well management anxiety, migraine glaucoma. Where known, mode action is from antagonism endogenous catecholamine responses (mainly at beta1-adrenoceptors), while worrisome side effects bronchospasm result airway beta2-adrenoceptor blockade. The aim this study was to determine selectivity beta-antagonists...
The Concise Guide to PHARMACOLOGY 2023/24 is the sixth in this series of biennial publications. provides concise overviews, mostly tabular format, key properties approximately 1800 drug targets, and about 6000 interactions with 3900 ligands. There an emphasis on selective pharmacology (where available), plus links open access knowledgebase source targets their ligands ( https://www.guidetopharmacology.org ), which more detailed views target ligand properties. Although constitutes almost 500...
β-Blockers have beneficial effects in heart failure, although the underlying mechanism is unknown. β<sub>2</sub>-Adrenoceptors, however, are proportionally higher failing human heart. This study shows several clinically used β-blockers agonists at β<sub>2</sub>-adrenoceptor. Although these agonist were small cAMP level, they substantial level of response element (CRE)-mediated gene transcription. Some “β-blockers” seen failure may be related to β<sub>2</sub>-agonist actions compounds....
The introduction of fluorescence-based techniques, and in particular the development fluorescent ligands, has allowed study G protein-coupled receptor pharmacology at single cell molecule level. This evaluated how physicochemical nature linker fluorophore affected pharmacological properties agonists antagonists.Chinese hamster ovary cells stably expressing human adenosine A(1) a cyclic 3',5' monophosphate response element-secreted placental alkaline phosphatase (CRE-SPAP) reporter gene,...
Fluorescence spectroscopy is becoming a valuable addition to the array of techniques available for scrutinizing ligand−receptor interactions in biological systems. In particular, scanning confocal microscopy and fluorescence correlation (FCS) allow noninvasive imaging quantification these single living cells. To address emerging need fluorescently labeled ligands support technologies, we have developed series red-emitting agonists human adenosine A1-receptor that, collectively, are...
Abstract α1‐adrenoceptor antagonists are widely used for hypertension (eg, doxazosin) and benign prostatic hypertrophy (BPH, eg, tamsulosin). Some antidepressants antipsychotics have been reported to α1 affinity. This study examined 101 clinical drugs laboratory compounds build a comprehensive understanding of subtype affinity selectivity. [3H]prazosin whole‐cell binding was conducted in CHO cells stably expressing either the full‐length human α1A, α1B, or α1D‐adrenoceptor. As expected,...
Inadequate and excessive gestational weight gain (GWG) defined by the Institute of Medicine (IOM) has been associated with preterm birth. However, studies demonstrate inconsistent associations. We examined associations between categorical continuous total GWG moderate to late birth (32-<37 weeks), evaluated differences in these pre-pregnancy BMI. analyzed cross-sectional data from children participating TARGet Kids! Toronto, Canada. Parents < 6 years age recalled weight, end-of-pregnancy...
Previous work with 4-[3-[(1,1-dimethylethyl)amino]2-hydroxypropoxy]-1,3-dihydro-2H-benzimidazol-2-one (CGP 12177) has led to the suggestion that there are two different agonist conformations of human β<sub>1</sub>-adrenoceptor: 1) where classic agonists (catecholamines) and β-antagonists act, 2) CGP 12177 is an relatively resistant inhibition by β-adrenoceptor antagonists. In present study, we have used studies cAMP response element-regulated gene transcription confirm presence these...
The growing practice of exploiting noninvasive fluorescence-based techniques to study G protein-coupled receptor pharmacology at the single cell and molecule level demands availability high-quality fluorescent ligands. To this end, evaluated a new series red-emitting ligands for human β-adrenoceptor family. Upon basis orthosteric propranolol, alprenolol, pindolol, synthesized linker-modified congeners were coupled commercially available fluorophore BODIPY 630/650-X. This yielded...
At the β1-adrenoceptor, CGP 12177 potently antagonizes agonist responses at primary high-affinity catecholamine conformation while also exerting effects of its own through a secondary low-affinity conformation. A recent mutagenesis study identified transmembrane region (TM)4 β1-adrenoceptor as key for this Others suggested that TM4 has role in oligomerization. Here, assessment dissociation rate fluorescent analog [bordifluoropyrromethane-tetramethylrhodamine-(±)CGP (BODIPY-TMR-CGP)] human...
α2-adrenoceptors, (α2A, α2B and α2C-subtypes), are Gi-coupled receptors. Central activation of brain α2A α2C-adrenoceptors is the main site for α2-agonist mediated clinical responses in hypertension, ADHD, muscle spasm ITU management sedation, reduction opiate requirements, nausea delirium. However, despite having same Gi-potency functional assays, some α2-agonists also stimulate Gs-responses whilst others do not. This was investigated. Agonist to 49 different α-agonists were studied...
Abstract α2‐Adrenoceptors, subdivided into α2A, α2B, and α2C subtypes expressed in heart, blood vessels, kidney, platelets brain, are important for pressure, sedation, analgesia, platelet aggregation. Brain α2C‐adrenoceptor blockade has also been suggested to be beneficial antipsychotic action. However, comparing α2‐adrenoceptor subtype affinity is difficult due significant species methodology differences published studies. Here, 3 H‐rauwolscine whole cell binding was used determine the...
The ability of an antagonist to bind a receptor is innate property that ligand-receptor chemical interaction. Provided no change in the or nature occurs, this affinity should remain constant for given antagonist-receptor interaction, regardless agonists used. This fundamental assumption underpins classification receptors. Here, measurements β<sub>2</sub>-adrenoceptor-mediated cAMP accumulation and response-element (CRE)-mediated reporter-gene transcription revealed differences depended upon...
Comparisons between structures of the β1-adrenergic receptor (AR) bound to either agonists, partial or weak agonists led proposal that rotamer changes Ser(5.46), coupled a contraction binding pocket, are sufficient increase probability activation. (RS)-4-[3-(tert-butylamino)-2-hydroxypropoxy]-1H-indole-2-carbonitrile (cyanopindolol) is agonist β1AR and, based on hypothesis above, we predicted addition methyl group form...
It has recently been reported that CGP 12177 can act as an agonist at a novel secondary site within the human β 1 ‐adrenoceptor. The aim of this study was to undertake detailed pharmacological effects on 2 acted potent partial 3 H‐cyclic AMP accumulation (log EC 50 −8.90±0.06) and CRE‐mediated reporter gene transcription −9.66±0.04) in CHO‐K1 cells expressing These CGP‐induced responses were antagonized by ‐selective antagonist ICI 118551 (apparent log K D values −8.84±0.15 −9.51±0.02 for...