Abstract:
:Identifying novel mechanisms to enhance glucagon-like peptide-1 (GLP-1) receptor signaling may enable nascent medicinal chemistry strategies with the aim of developing new orally available therapeutic agents for the treatment of type 2 diabetes mellitus. Therefore, we tested the hypothesis that selectively modulating the low-affinity GLP-1 receptor agonist, oxyntomodulin, would improve the insulin secretory properties of this naturally occurring hormone to provide a rationale for pursuing an unexplored therapeutic approach. Signal transduction and competition binding studies were used to investigate oxyntomodulin activity on the GLP-1 receptor in the presence of the small molecule GLP-1 receptor modulator, 4-(3-benzyloxyphenyl)-2-ethylsulfinyl-6-(trifluoromethyl)pyrimidine (BETP). In vivo, the intravenous glucose tolerance test characterized oxyntomodulin-induced insulin secretion in animals administered the small molecule. BETP increased oxyntomodulin binding affinity for the GLP-1 receptor and enhanced oxyntomodulin-mediated GLP-1 receptor signaling as measured by activation of the α subunit of heterotrimeric G protein and cAMP accumulation. In addition, oxyntomodulin-induced insulin secretion was enhanced in the presence of the compound. BETP was pharmacologically characterized to induce biased signaling by oxyntomodulin. These studies demonstrate that small molecules targeting the GLP-1 receptor can increase binding and receptor activation of the endogenous peptide oxyntomodulin. The biased signaling engendered by BETP suggests that GLP-1 receptor mobilization of cAMP is the critical insulinotropic signaling event. Because of the unique metabolic properties of oxyntomodulin, identifying molecules that enhance its activity should be pursued to assess the efficacy and safety of this novel mechanism.
journal_name
Mol Pharmacoljournal_title
Molecular pharmacologyauthors
Willard FS,Wootten D,Showalter AD,Savage EE,Ficorilli J,Farb TB,Bokvist K,Alsina-Fernandez J,Furness SG,Christopoulos A,Sexton PM,Sloop KWdoi
10.1124/mol.112.080432subject
Has Abstractpub_date
2012-12-01 00:00:00pages
1066-73issue
6eissn
0026-895Xissn
1521-0111pii
mol.112.080432journal_volume
82pub_type
杂志文章abstract::To determine the relationship between vascular alpha 1-adrenergic receptor occupancy and receptor-coupled calcium flux, we have studied [3H]prazosin binding and l-norepinephrine-induced 45Ca efflux in cultured vascular smooth muscle cells isolated from the rabbit aorta. In a crude cellular homogenate, [3H]prazosin bou...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1985-05-01 00:00:00
abstract::We have previously reported that endocytic sorting of ET(A) endothelin receptors to the recycling pathway is dependent on a signal residing in the cytoplasmic carboxyl-terminal region. The aim of the present work was to characterize the carboxyl-terminal recycling motif of the ET(A) receptor. Assay of truncation mutan...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.104.007013
更新日期:2005-05-01 00:00:00
abstract::The deletion of Phe-508 (DeltaPhe508) constitutes the most prevalent of a number of mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) that cause cystic fibrosis (CF). This mutation leads to CFTR misfolding and retention in the endoplasmic reticulum, as well as impaired channel activity. The b...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.109.055608
更新日期:2009-06-01 00:00:00
abstract::Mitochondria contain specific Ca2+ antagonist binding sites that are associated with an inner mitochondrial membrane anion channel. These mitochondrial Ca2+ antagonist receptors can be solubilized with digitonin and partially purified [as assessed by postreversible (+/-)-[3H]nitrendipine binding] using ion exchange ch...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1992-12-01 00:00:00
abstract::Differential display reverse transcription-polymerase chain reaction was used to identify mRNAs that are differentially expressed in the brain of rats treated chronically with the reference tricyclic antidepressant, imipramine, in comparison with control rats. The gene encoding for a mutation suppressor for Sec4-8 yea...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.62.6.1332
更新日期:2002-12-01 00:00:00
abstract::Cultured murine hepatoma 1c1c7 cells were treated with either the actin filament-disrupting drug cytochalasin D or the microtubule inhibitors colchicine and nocadazole (NOC) to assess the role of the cytoskeleton in the process of cytochrome P450 Cyp1a-1 induction. Indirect fluorescence analyses demonstrated that micr...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1994-05-01 00:00:00
abstract::Glioma cells with stem cell properties, termed glioma stem-like cells (GSCs), have been linked to tumor formation, maintenance, and progression and are responsible for the failure of chemotherapy and radiotherapy. Because conventional glioma treatments often fail to eliminate GSCs completely, residual surviving GSCs a...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.112.078402
更新日期:2012-09-01 00:00:00
abstract::Electron affinities, approximated by lowest unoccupied molecular orbital (LUMO) energies, were determined for an extensive group of nitrated polycyclic aromatic hydrocarbons by ab initio methods at the STO-3G level. Significant correlations were demonstrated between nitroarene LUMO energy and the corresponding mutagen...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1986-06-01 00:00:00
abstract::Molecular cloning of membrane-spanning mammalian adenylyl cyclases (ACs) has led to the discovery of nine different isotypes, making ACs potentially useful therapeutic targets. This study investigated the mechanism by which fungicidal nitroimidazole compounds modulate AC activity. Current evidence indicates that biolo...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.63.3.624
更新日期:2003-03-01 00:00:00
abstract::Combinations of coimmunoprecipitation, single-cell fluorescence resonance energy transfer, and cell-surface time-resolved fluorescence resonance energy transfer demonstrated protein-protein interactions and quaternary structure for the alpha(1b)-adrenoceptor. Self-association of transmembrane domain 1 and its interact...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.104.001586
更新日期:2004-11-01 00:00:00
abstract::The ability of dopamine agonists and antagonists to compete with [3H]spiperone binding to rat striatal membrane preparations at 4, 15, 26, and 37 degrees varied markedly with temperature. Dopamine and the dopamine agonist 2-amino-6,7-dihydroxy-1,2,3,4-tetrahydronaphthalene hydrobromide (ADTN) were more potent at lower...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1986-09-01 00:00:00
abstract::We examined the influence of the molecular structure of four novel adamantane derivatives on their ability to block the channels of nicotinic acetylcholine (ACh) and N-methyl-D-aspartate (NMDA) receptors. The structure of the drugs is Ad-CH2-N+H2-(CH2)5-R, where Ad is adamantane and R was varied from ammonium (IEM-175...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1995-03-01 00:00:00
abstract::[3H]P1075 binding to membrane preparations of rabbit skeletal muscle were observed in the presence of nucleotide triphosphates or diphosphates but not AMP, cAMP, adenosine, tripolyphosphate, or pyrophosphate. Nonhydrolyzable or poorly hydrolyzable ATP analogs inhibited MgATP-supported binding. The EC50 value for MgATP...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.52.3.473
更新日期:1997-09-01 00:00:00
abstract::We examined the effects on allosteric modulation and ligand binding of the mutation of amino acid residues of the human A(3) adenosine receptor (A(3)AR) that are hypothesized to be near one of three loci: the putative sodium binding site, the putative ligand binding site, and the DRY motif in transmembrane helical dom...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.63.5.1021
更新日期:2003-05-01 00:00:00
abstract::Neuroactive steroids have been postulated to cause anesthesia by binding to unique steroid recognition sites on gamma-aminobutyric acid (GABA) receptors and modulating GABA receptor function. Steroids interact with these sites diastereoselectively, but it is unknown whether steroid sites show enantioselectivity. To ad...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1996-12-01 00:00:00
abstract::Thyrotropin-releasing hormone (TRH) receptors were solubilized from a rat pituitary tumor cell line, GH4C1, with digitonin. Convenient assays were developed based on the ability of hydroxylapatite and polyethyleneimine-soaked glass fiber filters to adsorb the solubilized [3H]methyl-TRH-receptor complex but not free [3...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1989-04-01 00:00:00
abstract::The insecticide imidacloprid and structurally related neonicotinoids act selectively on insect nicotinic acetylcholine receptors (nAChRs). To investigate the mechanism of neonicotinoid selectivity, we have examined the effects of mutations to basic amino acid residues in loop D of the nAChR acetylcholine (ACh) binding...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.106.026815
更新日期:2006-10-01 00:00:00
abstract::1-[6-[[(17beta)-3-methoxyestra-1,3,5(10)-trien-17-yl]amino]hexyl]-1H-pyrrole-2,5-dione (U73122) is widely used to inhibit phospholipase C (PLC)-mediated signaling, but we and others have also reported a PLC-independent block of Kir3 channels in native cells. To elaborate on this major side effect, we examined the acti...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.108.047837
更新日期:2008-11-01 00:00:00
abstract::We have, in the accompanying work, demonstrated the coexistence of M2 and M3 muscarinic receptors in the circular smooth muscle of canine colon. In the present study, the effects of muscarinic receptor stimulation on phosphoinositide turnover and adenylate cyclase activity were examined. In myo-[3H]inositol-labeled ci...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1991-12-01 00:00:00
abstract::Dantrolene was recently identified as a novel inhibitor of the plasmodial surface anion channel (PSAC), an unusual ion channel on Plasmodium falciparum-infected human red blood cells. Because dantrolene is used clinically, has a high therapeutic index, and has desirable chemical synthetic properties, it may be a lead ...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.104.010553
更新日期:2005-07-01 00:00:00
abstract::Neuromedin U (NmU) is a 25 amino acid peptide prominently expressed in the upper gastrointestinal (GI) tract and central nervous system. It is highly conserved throughout evolution and induces smooth muscle contraction in a variety of species. Our understanding of NmU biology has been limited because the identity of i...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.58.4.870
更新日期:2000-10-01 00:00:00
abstract::The verapamil-like arylazide (-)-[3H]azidopamil specifically photoaffinity labeled two low molecular mass polypeptides, with apparent molecular masses of 22 and 27 kDa, in the endoplasmic reticulum of guinea pig liver, kidney, adrenal gland, and lung. It was recently shown that the 22-kDa polypeptide binds the anti-is...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1993-11-01 00:00:00
abstract::Excitotoxin-induced destruction of striatal neurons, proposed as a model of Huntington's disease, involves a process having the biochemical stigmata of apoptosis. Recent studies suggested that transcription factor nuclear factor (NF)-kappa B may be involved in excitotoxicity. To further analyze the contribution of NF ...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.53.1.33
更新日期:1998-01-01 00:00:00
abstract::The effects of the dihydropyridine calcium channel agonist Bay K 8644 on indo-1-loaded Jurkat human leukemia T lymphocytes was assessed by flow cytometry. Bay K 8644 from 10(-9) to 10(-4) M caused a dose-dependent rise in the intracellular free Ca concentration, an effect that was not mimicked by the dihydropyridine C...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1988-09-01 00:00:00
abstract::We have previously reported that, depending on the dose, nitric oxide (NO)-generating agents exert a dual facilitatory and inhibitory action on glutamatergic transmission on the rostral ventrolateral medulla (RVLM) neurons. The molecular mechanisms underlying the NO-mediated synaptic inhibition have not yet been defin...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.104.000554
更新日期:2004-09-01 00:00:00
abstract::PC-12 cells, derived from a rat pheochromocytoma, were found to take up tritiated serotonin ([3H]5-HT) from the external medium by means of a saturable mechanism which follows Michaelis-Menten kinetics. The apparent Km of uptake was 0.39 microM and the Vmax was 0.40 pmole/min/10(6) cells. The uptake was temperature-de...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1982-03-01 00:00:00
abstract::Effects of pimaric acid (PiMA) and eight closely related compounds on large-conductance K(+) (BK) channels were examined using human embryonic kidney (HEK) 293 cells, in which either the alpha subunit of BK channel (HEKBKalpha) or both alpha and beta1 (HEKBKalphabeta1) subunits were heterologously expressed. Effects o...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.62.4.836
更新日期:2002-10-01 00:00:00
abstract::Undesired block of human ERG1 potassium channels is the basis for cardiac side effects of many different types of drugs. Therefore, it is important to know exactly why some drugs particularly bind to these channels with high affinity. Upon expression in mammalian cells and Xenopus laevis oocytes, we investigated the i...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.65.5.1120
更新日期:2004-05-01 00:00:00
abstract::The possibility that vasoactive intestinal polypeptide (VIP) may facilitate the nicotine-mediated induction of adrenal medullary tyrosine hydroxylase (TH) was investigated with primary cultures (5-7 days in vitro) of bovine adrenal chromaffin (BAC) cells. Exposure of BAC cells to 100 microM nicotine led to only a marg...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1992-03-01 00:00:00
abstract::A family of five cholinergic muscarinic receptor genes (m1, m2, m3, m4, and m5) has recently been identified and cloned. In order to investigate the pharmacological properties of the individual muscarinic receptors, we have transfected each of these genes into Chinese hamster ovary cells (CHO-K1) and have established ...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1989-04-01 00:00:00