A5020423575- Receptor Mechanisms and Signaling
- Neuropeptides and Animal Physiology
- Pharmacological Receptor Mechanisms and Effects
- Pain Mechanisms and Treatments
- Nicotinic Acetylcholine Receptors Study
- Chemical Synthesis and Analysis
- Neuroscience and Neuropharmacology Research
- Neurotransmitter Receptor Influence on Behavior
- Ion channel regulation and function
- Hypothalamic control of reproductive hormones
- Pharmacological Effects and Assays
- Synthesis and Biological Evaluation
- Cancer, Stress, Anesthesia, and Immune Response
- Analytical Chemistry and Chromatography
- Migraine and Headache Studies
- Sleep and Wakefulness Research
- Synthesis and pharmacology of benzodiazepine derivatives
- Computational Drug Discovery Methods
- Protein Hydrolysis and Bioactive Peptides
- Crystallization and Solubility Studies
- Mast cells and histamine
- Cholinesterase and Neurodegenerative Diseases
- Regulation of Appetite and Obesity
- Biochemical Analysis and Sensing Techniques
- Cardiac electrophysiology and arrhythmias
Florida Atlantic University
2018-2024
SRI International
2005-2023
Torrey Pines Institute For Molecular Studies
2012-2019
University of Ferrara
2016-2018
Assuage Pharmaceuticals (United States)
2017-2018
Uniformed Services University of the Health Sciences
2016
Astraea Therapeutics (United States)
2009-2016
Washington University in St. Louis
2016
University of Bath
2013
Northeastern University
2013
ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTRole of Mg2+ion-activated ATPase and a pH gradient in the storage catecholamines synaptic vesiclesLawrence Toll Bruce D. HowardCite this: Biochemistry 1978, 17, 13, 2517–2523Publication Date (Print):June 27, 1978Publication History Published online1 May 2002Published inissue 27 June 1978https://pubs.acs.org/doi/10.1021/bi00606a010https://doi.org/10.1021/bi00606a010research-articleACS PublicationsRequest reuse permissionsArticle...
Fifteen hexapeptides having high affinity for the opioid-like receptor ORL1 were identified from a combinatorial library containing more than 52 million different hexapeptides. The five compounds with highest characterized further by use of variety in vitro models. Binding studies indicated that these peptides have nanomolar range, similar to recently discovered endogenous ligand called nociceptin and orphanin FQ (N/OFQ). activity was investigated three assays: stimulation [35S]GTPgammaS...
PC12 cells, a clonal rat pheochromocytoma cell line, possess voltage-dependent calcium channels that bind the high affinity dihydropyridine antagonist [3H]nitrendipine and other channel blockers. The binding is temperature-dependent saturable, shows no cooperativity. antagonists inhibit potassium-induced 45Ca uptake into cells with approximately same potencies as those needed to membranes. of these compounds for slightly lower than reported brain heart. Potassium-stimulated rapid, being...
ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTStorage of dopamine and acetylcholine in granules PC12, a clonal pheochromocytoma cell lineRobert V. Rebois, Elwood E. Reynolds, Lawrence Toll, Bruce D. HowardCite this: Biochemistry 1980, 19, 6, 1240–1248Publication Date (Print):March 18, 1980Publication History Published online1 May 2002Published inissue 18 March 1980https://pubs.acs.org/doi/10.1021/bi00547a031https://doi.org/10.1021/bi00547a031research-articleACS PublicationsRequest reuse...
Stress-induced analgesia (SIA) is a key component of the defensive behavioral "fight-or-flight" response. Although neural substrates SIA are incompletely understood, previous studies have implicated hypocretin/orexin (Hcrt) and nociceptin/orphanin FQ (N/OFQ) peptidergic systems in regulation SIA. Using immunohistochemistry brain tissue from wild-type mice, we identified N/OFQ-containing fibers forming synaptic contacts with Hcrt neurons at both light electron microscopic levels. Patch clamp...
PC12, a clonal line of rat pheochromocytoma, accumulates newly synthesized acetylcholine in storage granules.The accumulation PC12 granules, but not synthesis, was inhibited by treatment the cells with any several inhibitors energy metabolism.These included nigericin, carbonyl cyanidep-trifluoromethoxyphenylhydrazone, dicyclohexylcarbodiimide, and iodoacetate.Valinomycin alone oligomycin were without effect.Except f o r iodoacetate, these agents did exert their effects on depleting...
There are currently a large number of "orphan" G-protein-coupled receptors (GPCRs) whose endogenous ligands (peptide hormones) unknown. Identification these peptide hormones is difficult and important problem. We describe computational framework that models spatial structure along the genomic sequence simultaneously with temporal evolutionary path across species show how such can be used to discover new functional molecules, in particular hormones, via cross-genomic comparisons. The...
Computational methods have led two groups to predict the endogenous presence of a highly conserved, amidated, 14-aa neuropeptide called either spexin or NPQ. NPQ/spexin is part larger prohormone that contains 3 sets RR residues, suggesting it could yield more than one bioactive peptide; however, no in vivo activity has been demonstrated for any peptide processed from this precursor. Here we demonstrate biological peptides present within proNPQ/spexin. (NWTPQAMLYLKGAQ-NH2) and NPQ 53–70...
The κ receptor has a central role in modulating neurotransmission and peripheral neuronal circuits that subserve pain other behavioural responses. Although agonists do not produce euphoria or lead to respiratory suppression, they induce dysphoria sedation. We hypothesized brain-penetrant ligands possessing biased agonism towards G protein signalling over β-arrestin2 recruitment would robust antinociception with fewer associated liabilities.
Quantitative peptidomics was used to compare levels of peptides in wild type (WT) and Cpe(fat/fat) mice, which lack carboxypeptidase E (CPE) activity because a point mutation. Six different brain regions were analyzed: amygdala, hippocampus, hypothalamus, prefrontal cortex, striatum, thalamus. Altogether, 111 neuropeptides or other derived from secretory pathway proteins identified WT mouse extracts by tandem mass spectrometry, another 47 tentatively based on criteria. Most much lower brain,...
The nociceptin receptor (NOPr), a member of the opioid family, is target for treatment pain and drug abuse. Nociceptin/orphanin FQ (N/OFQ), endogenous peptide NOPr, not only modulates antinociception, but also blocks rewarding effects several abused drugs, such as morphine, cocaine, amphetamine. We hypothesized that NOPr agonists, with bifunctional activity at μ-opioid (MOPr), may function nonaddicting analgesics or abuse medications. Bifunctional small-molecule agonists possessing different...
Activation of brain nociceptin/orphanin FQ (NOP) receptors leads to attenuation μ-opioid receptor (MOP receptor)-mediated antinociception. Buprenorphine, a high-affinity partial MOP agonist also binds NOP with 80 nM affinity. The buprenorphine-induced inverted U-shaped dose-response curve for antinociception may be due activation, given that, in the presence antagonist, 1-[(3<i>R</i>,4<i>R</i>)-1-cyclooctylmethyl-3-hydroxymethyl-4-piperidyl]-3-ethyl-1,3-dihydro-2<i>H</i>-benzimidazol-2-one...
Certain behavioral features of buprenorphine, including a bell-shaped curve for antinociception and attenuation alcohol consumption, are thought to be mediated by activation nociceptin/orphanin FQ peptide (NOP) receptors, despite moderate affinity low efficacy at NOP receptors. We hypothesized that ligands with buprenorphine's physical properties, but possessing increased receptor efficacy, would improve the profile as drug abuse medication reduce addiction liability. Using this strategy, we...
The nociceptin/orphanin FQ (NOP) receptor, the fourth member of opioid receptor family, is involved in many processes common to receptors including pain and drug abuse. To better characterize location trafficking, knock-in mice were created by inserting gene encoding enhanced green fluorescent protein (eGFP) into NOP (<i>Oprl1</i>) producing expressing a functional NOP-eGFP C-terminal fusion place native receptor. was present brain homozygous animals concentrations somewhat higher than...
Doxorubicin (DXR) is an effective antitumor agent in a wide spectrum of neoplasms. Chronic treatment associated with cardiomyopathy and characteristic myocardial ultrastructural changes, which include swelling the t tubules. Accordingly, we investigated excitation-contraction coupling cardiomyopathic rat heart resulting from chronic DXR treatment. Using whole-cell patch clamp technique, studied L-type calcium channel single cells enzymatically isolated normal (CTRL) hearts. Despite similar...
1-(1-Cyclooctylpiperidin-4-yl)-indolin-2-one (SR14150) and 1-(1-(2,3,3a,4,5,6-hexahydro-1H-phenalen-1-yl)piperidinl-4-yl)-indolin-2-one (SR16835) are moderately selective nociceptin/orphanin FQ (NOP) receptor agonists. In the [(35)S]guanosine 5'-O-(3-thiotriphosphate) assay in vitro, SR14150 is a partial agonist at both NOP μ-opioid receptors, whereas SR16835 full has low efficacy μ receptors. These compounds were tested for antinociceptive antiallodynic activity, using mice chronic pain,...