Atropine blockade of cholinergic drugs on rabbit stomach muscle

1978 ◽  
Vol 56 (5) ◽  
pp. 873-876 ◽  
Author(s):  
L. Spero
Keyword(s):  
Smooth Muscle ◽  
Partial Agonist ◽  
Affinity Constant ◽  
Stomach Muscle ◽  
Competitive Effect ◽  
Full Agonist ◽  
Cholinergic Drugs ◽  
Partial Agonists

The competition between atropine and a full agonist, carbachol, was tested on dibenamine-pretreated smooth muscle of rabbit stomach. Even after extensive irreversible blockade by dibenamine, atropine blockade of the response to carbachol was still competitive and the atropine affinity constant was unchanged. This differed from the noncompetitive action of atropine in blocking the contractile effects of partial agonists such as pilocarpine or heptyl trimethylammonium. The results thus indicate that it is not possible to convert a full agonist into a partial agonist merely by reducing the number of available cholinergic receptors.The present study compares the competitive effect of atropine on the actions of the full agonist carbachol, under conditions of irreversible blockade, with the competitive effect of atropine on partial agonists such as pilocarpine or heptyl trimethylammonium.

scholarly journals Identification of new gonadotrophin-releasing hormone partial agonists

2006 ◽  
Vol 189 (3) ◽  
pp. 509-517 ◽  
Author(s):  
Alfredo Leaños-Miranda ◽  
Alfredo Ulloa-Aguirre ◽  
Laura A Cervini ◽  
Jo Ann Janovick ◽  
Jean Rivier ◽  
...  
Keyword(s):  
Inositol Phosphate ◽  
Partial Agonist ◽  
Prolonged Treatment ◽  
Complete Suppression ◽  
Antagonist Activity ◽  
Gnrh Analogues ◽  
Full Agonist ◽  
Partial Agonists ◽  
Stimulation Of

GnRH agonists or antagonists are currently utilized as therapeutic agents in a number of diseases. A side-effect of prolonged treatment with GnRH analogues is hypoestrogenism. In this study, we tested the in vitro potency of different GnRH analogues originally found to be partial agonists (i.e. analogues with decreased efficacy for activating or stimulating their cognate receptor) as well as novel analogues, to identify compounds that might potentially be useful for partial blockade of gonadotrophin release. Cultured COS-7 cells transiently expressing the rat or human GnRH receptor (GnRHR) were exposed to increasing concentrations (10−8 to 10−5 M) of GnRH analogues (c(4–10)[Asp4,DNal6,Dpr10]-GnRH; c(4–10) [Dpr4,DNal6,Asp10]-GnRH; c(4–10)[Cys4,10,DNal6]-GnRH; c[Eaca1,DNal6]-GnRH; c[Gly1,DNal6]-GnRH; c[βAla1,DTrp6]-GnRH; c[Dava1,DNal6]-GnRH; c[Gaba1, DNal6]-GnRH), and the ability of these analogues to provoke or antagonize GnRH-stimulated inositol phosphate production was assessed. With both human and rat GnRHRs, c[Eaca1,DNal6]-GnRH, c[Gly1,DNal6]-GnRH, c[βAla1,DTrp6]-GnRH and c[Dava1,DNal6]-GnRH exhibited partial agonist activity (35–87% of the maximal efficacy shown by 10−6 M GnRH), whereas c[Gaba1,DNal6]-GnRH behaved as a partial agonist with the human GnRHR and as full agonist with the rat GnRHR. c(4–10)[Asp4, DNal6,Dpr10]-GnRH and c(4–10)[Dpr4,DNal6,Asp10]-GnRH exhibited full antagonist activity with both GnRHRs, and c(4–10) [Cys4,10,DNal6]-GnRH was a weak, partial agonist with the human GnRHR and a full antagonist with the rat GnRHR. With the exception of c[Gaba1,DNal6]-GnRH stimulation of the human GnRHR, and c[Dava1,DNal6]-GnRH and c[Gaba1, DNal6]-GnRH stimulation of the rat GnRHR, all partial agonists also exhibited antagonist activity in the presence of the exogenous full agonist. The results demonstrate that structurally similar analogues display variable potencies and efficacies in vitro for a specific GnRHR as well as for the human versus the rat GnRHR. Their ultimate in vivo usefulness to treat clinical conditions in which complete suppression of gonadotroph activity is not required remains to be investigated.

scholarly journals Predicting the Activation of the Androgen Receptor by Mixtures of Ligands Using Generalized Concentration Addition

2020 ◽  
Vol 177 (2) ◽  
pp. 466-475 ◽  
Author(s):  
Jennifer J Schlezinger ◽  
Wendy Heiger-Bernays ◽  
Thomas F Webster
Keyword(s):  
Androgen Receptor ◽  
Partial Agonist ◽  
Pharmacodynamic Model ◽  
Concentration Addition ◽  
Receptor Ligands ◽  
Receptor System ◽  
Competitive Antagonist ◽  
Full Agonist ◽  
Response Data ◽  
Partial Agonists

Abstract Concentration/dose addition is widely used for compounds that act by similar mechanisms. But it cannot make predictions for mixtures of full and partial agonists for effect levels above that of the least efficacious component. As partial agonists are common, we developed generalized concentration addition, which has been successfully applied to systems in which ligands compete for a single binding site. Here, we applied a pharmacodynamic model for a homodimer receptor system with 2 binding sites, the androgen receptor, that acts according to the classic homodimer activation model: Each cytoplasmic monomer protein binds ligand, undergoes a conformational change that relieves inhibition of dimerization, and binds to DNA response elements as a dimer. We generated individual dose-response data for full (dihydroxytestosterone, BMS564929) and partial (TFM-4AS-1) agonists and a competitive antagonist (MDV3100) using reporter data generated in the MDA-kb2 cell line. We used the Schild method to estimate the binding affinity of MDV3100. Data for individual compounds fit the homodimer pharmacodynamic model well. In the presence of a full agonist, the partial agonist had agonistic effects at low effect levels and antagonistic effects at high levels, as predicted by pharmacological theory. The generalized concentration addition model fits the empirical mixtures data—full/full agonist, full/partial agonist, and full agonist/antagonist—as well or better than relative potency factors or effect summation. The ability of generalized concentration addition to predict the activity of mixtures of different types of androgen receptor ligands is important as a number of environmental compounds act as partial androgen receptor agonists or antagonists.

α1-Adrenergic partial agonists utilize cytosolic Ca2+ more effectively for contraction in aortic smooth muscle

1990 ◽  
Vol 68 (10) ◽  
pp. 1329-1333 ◽  
Author(s):  
Issei Takayanagi ◽  
Shuji Onozuka
Keyword(s):  
Smooth Muscle ◽  
Key Words ◽  
Thoracic Aorta ◽  
Partial Agonist ◽  
Muscle Tension ◽  
Dependent Manner ◽  
Concentration Dependent Manner ◽  
Tension Development ◽  
Aortic Smooth Muscle ◽  
Partial Agonists

Fura 2 loaded thoracic aorta strips from rabbits were used. Norepinephrine, phenylephrine, clonidine, and tizanidine induced an increase in cytosolic Ca2+ concentration ([Ca2+]i) and muscle tension in a concentration-dependent manner. A positive correlation between [Ca2+]i and tension development owing to the agonists was noted. The slope of regression lines between [Ca2+]i and tension development for clonidine and tizanidine, α1-adrenergic partial agonists, were significantly steeper than those for norepinephrine and phenylephrine, α1-adrenergic full agonists. The intrinsic activities of the partial agonists obtained from tension development were greater than those from changes in [Ca2+]i. These results suggest that the partial agonists cause a greater muscle tension than the full agonists at the same level of [Ca2+]i.Key words: cytosolic Ca2+ concentration, tension, partial agonist, full agonist,α1-adrenoceptors.

scholarly journals Predicting the activation of the androgen receptor by mixtures of ligands using Generalized Concentration Addition

2020 ◽  
Author(s):  
Jennifer J Schlezinger ◽  
Wendy Heiger-Bernays ◽  
Thomas F Webster
Keyword(s):  
Androgen Receptor ◽  
Partial Agonist ◽  
Pharmacodynamic Model ◽  
Model Fit ◽  
Concentration Addition ◽  
Receptor Ligands ◽  
Competitive Antagonist ◽  
Full Agonist ◽  
Response Data ◽  
Partial Agonists

AbstractConcentration/dose addition (CA) is widely used for compounds that act by similar mechanisms. But, CA cannot make predictions for mixtures of full and partial agonists for effect levels above that of the least efficacious component. As partial agonists are common, we developed Generalized Concentration Addition (GCA), which has been successfully applied to systems in which ligands compete for a single binding site. Here, we applied a pharmacodynamic model for a system with two binding sites, the androgen receptor (AR). AR acts according to the classic homodimer activation model: each cytoplasmic AR protein binds ligand, undergoes a conformational change that relieves inhibition of dimerization, and binds to DNA response elements as a dimer. We generated individual dose-response data for full (dihydroxytestosterone, BMS564929) and partial (TFM-4AS-1) agonists and a competitive antagonist (MDV3100) using reporter data generated in the MDA-kb2 cell line. We used the Schild method to estimate the binding affinity of AR for MDV3100. Data for individual compounds fit the AR pharmacodynamic model well. The partial agonist had agonistic effects at low effect levels and antagonistic effects at high levels, as predicted by pharmacological theory. The GCA model fit the empirical mixtures data—full/full agonist, full/partial agonist and full agonist/antagonist—as well or better than relative potency factors (a special case of CA) or effect summation. The ability of generalized concentration addition to predict the activity of mixtures of different types of androgen receptor ligands is important as a number of environmental compounds act as partial AR agonists or antagonists.

scholarly journals Design, Synthesis and Pharmacological Profile of LUF7746, a Novel Covalent Partial Agonist for the Adenosine A1 Receptor

2020 ◽  
Author(s):  
Xue Yang ◽  
Majlen Dilweg ◽  
Dion Osemwengie ◽  
Lindsey Burggraaff ◽  
Daan van der Es ◽  
...  
Keyword(s):  
G Protein ◽  
Partial Agonist ◽  
Receptor Activation ◽  
Adenosine A1 Receptor ◽  
Activation Process ◽  
Full Agonist ◽  
Partial Agonists ◽  
Activation Assay ◽  
Adenosine A1 ◽  
A1 Receptor

Partial agonists for G protein-coupled receptors (GPCRs) provide opportunities for novel pharmacotherapies with enhanced on-target safety compared to full agonists. For the human adenosine A1 receptor (hA1AR) this has led to the discovery of capadenoson, which has been in phase IIa clinical trials for heart failure. Accordingly, the design and profiling of novel hA1AR partial agonists has become an important research focus. In this study, we report on LUF7746, a capadenoson derivative bearing an electrophilic fluorosulfonyl moiety, as an irreversibly binding hA1AR modulator. Meanwhile, a nonreactive ligand bearing a methylsulfonyl moiety, LUF7747, was designed as a control probe in our study. In a radioligand binding assay, LUF7746’s apparent affinity increased to nanomolar range with longer pre-incubation time, suggesting an increasing level of covalent binding over time. Moreover, compared to the reference full agonist CPA, LUF7746 was a partial agonist in a hA1AR-mediated G protein activation assay and resistant to blockade with an antagonist/inverse agonist. An in silico structure-based docking study combined with site-directed mutagenesis of the hA1AR demonstrated that amino acid Y2717.36 was the primary anchor point for the covalent interaction. Additionally, a label-free whole-cell assay was set up to identify LUF7746’s irreversible activation of an A1 receptor-mediated cell morphological response. These results led us to conclude that LUF7746 is a novel covalent hA1AR partial agonist and a valuable chemical probe for further mapping the receptor activation process. It may also serve as a prototype for a therapeutic approach in which a covalent partial agonist may cause less on-target side effects, conferring enhanced safety compared to a full agonist.<br>

Fluorescence Characteristics of Hydrophobic Partial Agonist Probes of the Cholecystokinin Receptor

2006 ◽  
Vol 26 (2) ◽  
pp. 89-100 ◽  
Author(s):  
Kaleeckal G. Harikumar ◽  
Delia I. Pinon ◽  
Laurence J. Miller
Keyword(s):  
Partial Agonist ◽  
Receptor Activation ◽  
Spectroscopic Studies ◽  
Dynamic Changes ◽  
Full Agonist ◽  
Cholecystokinin Receptor ◽  
Partial Agonists ◽  
Receptor Structure ◽  
Fluorescence Characteristics ◽  
Agonist And Antagonist

Fluorescence spectroscopic studies are powerful tools for the evaluation of receptor structure and the dynamic changes associated with receptor activation. Here, we have developed two chemically distinct fluorescent probes of the cholecystokinin (CCK) receptor by attaching acrylodan or a nitrobenzoxadiazole moiety to the amino terminus of a partial agonist CCK analogue. These two probes were able to bind to the CCK receptor specifically and with high affinity, and were able to elicit only submaximal intracellular calcium responses typical of partial agonists. The fluorescence characteristics of these probes were compared with those previously reported for structurally-related full agonist and antagonist probes. Like the previous probes, the partial agonist probes exhibited longer fluorescence lifetimes and increased anisotropy when bound to the receptor than when free in solution. The receptor-bound probes were not easily quenched by potassium iodide, suggesting that the fluorophores were protected from the extracellular aqueous milieu. The fluorescence characteristics of the partial agonist probes were quite similar to those of the analogous full agonist probes and quite distinct from the analogous antagonist probes. These data suggest that the partially activated conformational state of this receptor is more closely related to its fully active state than to its inactive state.

scholarly journals Design, Synthesis and Pharmacological Profile of LUF7746, a Novel Covalent Partial Agonist for the Adenosine A1 Receptor

2020 ◽  
Author(s):  
Xue Yang ◽  
Majlen Dilweg ◽  
Dion Osemwengie ◽  
Lindsey Burggraaff ◽  
Daan van der Es ◽  
...  
Keyword(s):  
G Protein ◽  
Partial Agonist ◽  
Receptor Activation ◽  
Adenosine A1 Receptor ◽  
Activation Process ◽  
Full Agonist ◽  
Partial Agonists ◽  
Activation Assay ◽  
Adenosine A1 ◽  
A1 Receptor

Partial agonists for G protein-coupled receptors (GPCRs) provide opportunities for novel pharmacotherapies with enhanced on-target safety compared to full agonists. For the human adenosine A1 receptor (hA1AR) this has led to the discovery of capadenoson, which has been in phase IIa clinical trials for heart failure. Accordingly, the design and profiling of novel hA1AR partial agonists has become an important research focus. In this study, we report on LUF7746, a capadenoson derivative bearing an electrophilic fluorosulfonyl moiety, as an irreversibly binding hA1AR modulator. Meanwhile, a nonreactive ligand bearing a methylsulfonyl moiety, LUF7747, was designed as a control probe in our study. In a radioligand binding assay, LUF7746’s apparent affinity increased to nanomolar range with longer pre-incubation time, suggesting an increasing level of covalent binding over time. Moreover, compared to the reference full agonist CPA, LUF7746 was a partial agonist in a hA1AR-mediated G protein activation assay and resistant to blockade with an antagonist/inverse agonist. An in silico structure-based docking study combined with site-directed mutagenesis of the hA1AR demonstrated that amino acid Y2717.36 was the primary anchor point for the covalent interaction. Additionally, a label-free whole-cell assay was set up to identify LUF7746’s irreversible activation of an A1 receptor-mediated cell morphological response. These results led us to conclude that LUF7746 is a novel covalent hA1AR partial agonist and a valuable chemical probe for further mapping the receptor activation process. It may also serve as a prototype for a therapeutic approach in which a covalent partial agonist may cause less on-target side effects, conferring enhanced safety compared to a full agonist.<br>

RXR Partial Agonist Produced by Side Chain Repositioning of Alkoxy RXR Full Agonist Retains Antitype 2 Diabetes Activity without the Adverse Effects

2014 ◽  
Vol 58 (2) ◽  
pp. 912-926 ◽  
Author(s):  
Kohei Kawata ◽  
Ken-ichi Morishita ◽  
Mariko Nakayama ◽  
Shoya Yamada ◽  
Toshiki Kobayashi ◽  
...  
Keyword(s):  
Adverse Effects ◽  
Partial Agonist ◽  
Side Chain ◽  
Full Agonist

scholarly journals GPR40 reduces food intake and body weight through GLP-1

2017 ◽  
Vol 313 (1) ◽  
pp. E37-E47 ◽  
Author(s):  
Judith N. Gorski ◽  
Michele J. Pachanski ◽  
Joel Mane ◽  
Christopher W. Plummer ◽  
Sarah Souza ◽  
...  
Keyword(s):  
Weight Loss ◽  
Body Weight ◽  
Food Intake ◽  
Partial Agonist ◽  
Glucose Lowering ◽  
Partial Agonists ◽  
Lower Glucose ◽  
Glucagon Like Peptide 1 ◽  
Glucose Stimulated Insulin Secretion ◽  
G Protein Coupled

G protein-coupled receptor 40 (GPR40) partial agonists lower glucose through the potentiation of glucose-stimulated insulin secretion, which is believed to provide significant glucose lowering without the weight gain or hypoglycemic risk associated with exogenous insulin or glucose-independent insulin secretagogues. The class of small-molecule GPR40 modulators, known as AgoPAMs (agonist also capable of acting as positive allosteric modulators), differentiate from partial agonists, binding to a distinct site and functioning as full agonists to stimulate the secretion of both insulin and glucagon-like peptide-1 (GLP-1). Here we show that GPR40 AgoPAMs significantly increase active GLP-1 levels and reduce acute and chronic food intake and body weight in diet-induced obese (DIO) mice. These effects of AgoPAM treatment on food intake are novel and required both GPR40 and GLP-1 receptor signaling pathways, as demonstrated in GPR40 and GLP-1 receptor-null mice. Furthermore, weight loss associated with GPR40 AgoPAMs was accompanied by a significant reduction in gastric motility in these DIO mice. Chronic treatment with a GPR40 AgoPAM, in combination with a dipeptidyl peptidase IV inhibitor, synergistically decreased food intake and body weight in the mouse. The effect of GPR40 AgoPAMs on GLP-1 secretion was recapitulated in lean, healthy rhesus macaque demonstrating that the putative mechanism mediating weight loss translates to higher species. Together, our data indicate effects of AgoPAMs that go beyond glucose lowering previously observed with GPR40 partial agonist treatment with additional potential for weight loss.

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