scholarly journals Species‐specific action of (Pro3)GIP – a full agonist at human GIP receptors, but a partial agonist and competitive antagonist at rat and mouse GIP receptors

2015 ◽  
Vol 173 (1) ◽  
pp. 27-38 ◽  
Author(s):  
A H Sparre‐Ulrich ◽  
L S Hansen ◽  
B Svendsen ◽  
M Christensen ◽  
F K Knop ◽  
...  
Keyword(s):  
Partial Agonist ◽  
Competitive Antagonist ◽  
Full Agonist ◽  
Species Specific

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.

scholarly journals A Robust Bioassay of the Human Bradykinin B2 Receptor that Extends Molecular and Cellular Studies: The Isolated Umbilical Vein

2021 ◽  
Vol 14 (3) ◽  
pp. 177
Author(s):  
François Marceau ◽  
Hélène Bachelard
Keyword(s):  
Partial Agonist ◽  
Umbilical Vein ◽  
In Vivo Studies ◽  
Molecular Pharmacology ◽  
Smooth Muscle Contractility ◽  
Competitive Antagonist ◽  
Pharmacological Agents ◽  
Species Specific ◽  
G Protein Coupled

Bradykinin (BK) has various physiological and pathological roles. Medicinal chemistry efforts targeted toward the widely expressed BK B2 receptor (B2R), a G-protein-coupled receptor, were primarily aimed at developing antagonists. The only B2R antagonist in clinical use is the peptide icatibant, approved to abort attacks of hereditary angioedema. However, the anti-inflammatory applications of B2R antagonists are potentially wider. Furthermore, the B2R antagonists notoriously exhibit species-specific pharmacological profiles. Classical smooth muscle contractility assays are exploited over a time scale of several hours and support determining potency, competitiveness, residual agonist activity, specificity, and reversibility of pharmacological agents. The contractility assay based on the isolated human umbilical vein, expressing B2R at physiological density, was introduced when investigating the first non-peptide B2R antagonist (WIN 64338). Small ligand molecules characterized using the assay include the exquisitely potent competitive antagonist, Pharvaris Compound 3 or the partial agonist Fujisawa Compound 47a. The umbilical vein assay is also useful to verify pharmacologic properties of special peptide B2R ligands, such as the carboxypeptidase-activated latent agonists and fluorescent probes. Furthermore, the proposed agonist effect of tissue kallikrein on the B2R has been disproved using the vein. This assay stands in between cellular and molecular pharmacology and in vivo studies.

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.

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

Abecarnil is a Full Agonist at Some, and a Partial Agonist at Other Recombinant GABAA Receptor Subtypes

1993 ◽  
pp. 50-61 ◽  
Author(s):  
I. Pribilla ◽  
R. Neuhaus ◽  
R. Huba ◽  
M. Hillmann ◽  
J. D. Turner ◽  
...  
Keyword(s):  
Gabaa Receptor ◽  
Partial Agonist ◽  
Receptor Subtypes ◽  
Full Agonist ◽  
Gabaa Receptor Subtypes

Antagonist, Partial Agonist, and Full Agonist Imidazo[1,5-a]quinoxaline Amides and Carbamates Acting through the GABAA/Benzodiazepine Receptor

1994 ◽  
Vol 37 (6) ◽  
pp. 758-768 ◽  
Author(s):  
Ruth E. TenBrink ◽  
Wha B. Im ◽  
Vimala H. Sethy ◽  
Andrew H. Tang ◽  
Don B. Carter
Keyword(s):  
Partial Agonist ◽  
Benzodiazepine Receptor ◽  
Full Agonist

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.

Steroidogenic activity of highly potent melanotropic peptides in the adrenal cortex of the rat

1986 ◽  
Vol 113 (3) ◽  
pp. 396-402 ◽  
Author(s):  
J. B. Baumann ◽  
A. N. Eberle ◽  
E. Christen ◽  
W. Ruch ◽  
J. Girard
Keyword(s):  
Adrenal Cortex ◽  
Partial Agonist ◽  
Pigment Cell ◽  
Cell Types ◽  
Activity Profile ◽  
Full Agonist ◽  
Acth Receptor ◽  
Cell Assays ◽  
Isolated Rat

Abstract. Highly purified ACTH and MSH peptides were studied in isolated rat glomerulosa and inner zone cells and their activity compared with that in an Anolis melanophore assay. While both ACTH1-39 and ACTH1-24 were almost equally potent steroidogenic peptides in the two cell types (ED50 between 1 and 4 × 10−12 m), α-MSH displayed only weak steroidogenic activity. Although it was a full agonist, it was about 104-fold less potent in both capsular and inner zone cells. β-MSH (porcine) was even 10-fold less active in capsular cells than α-MSH, and in inner zone cells it was a partial agonist. Highly potent melanotropic peptides, such as (Nle4, D-Phe7)-α-MSH or cyclic (Cys4, Cys10)-α-MSH were either inactive or exhibited only a very slight partial steroidogenic activity in both cell types. Comparison of the activity profile of additional compounds, such as des-acetyl α-MSH, (Tyr(I)2)-α-MSH, (Trp(For)9)-α-MSH or (Nva12-α-MSH in the adrenocortical and pigment cell assays led to the conclusion that α-MSH does not exert its steroidogenic effect through a typical melanocyte-type of MSH receptor, but rather through a low affinity-type of ACTH receptor.

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