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

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.

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

Acta Endocrinologica ◽

10.1530/acta.0.1130396 ◽

1986 ◽

Vol 113 (3) ◽

pp. 396-402 ◽

Cited By ~ 13

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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Different structures of the two peroxisome proliferator-activated receptor gamma (PPARγ) ligand-binding domains in homodimeric complex with partial agonist, but not full agonist

Bioorganic & Medicinal Chemistry Letters ◽

10.1016/j.bmcl.2015.04.076 ◽

2015 ◽

Vol 25 (13) ◽

pp. 2639-2644 ◽

Cited By ~ 7

Author(s):

Masao Ohashi ◽

Takuji Oyama ◽

Hiroyuki Miyachi

Keyword(s):

Ligand Binding ◽

Partial Agonist ◽

Peroxisome Proliferator ◽

Peroxisome Proliferator Activated Receptor ◽

Full Agonist ◽

Binding Domains

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

Toxicological Sciences ◽

10.1093/toxsci/kfaa108 ◽

2020 ◽

Vol 177 (2) ◽

pp. 466-475 ◽

Cited By ~ 1

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.

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Abecarnil: A Novel Anxiolytic with Mixed Full Agonist/Partial Agonist Properties in Animal Models of Anxiety and Sedation

Anxiolytic β-Carbolines ◽

10.1007/978-3-642-78451-4_7 ◽

1993 ◽

pp. 79-95 ◽

Cited By ~ 6

Author(s):

D. N. Stephens ◽

L. Turski ◽

G. H. Jones ◽

K. G. Steppuhn ◽

H. H. Schneider

Keyword(s):

Animal Models ◽

Partial Agonist ◽

Full Agonist ◽

Animal Models Of Anxiety

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Emerging pharmacologic mechanisms of buprenorphine to explain experience of analgesia versus adverse effects

Journal of Opioid Management ◽

10.5055/jom.2021.0639 ◽

2021 ◽

Vol 17 (7) ◽

pp. 21-31

Author(s):

Jeffrey Bettinger, PharmD ◽

Himayapsill Batista Quevedo, PharmD ◽

Jacqueline Cleary, PharmD, BCACP

Keyword(s):

Adverse Effects ◽

Opioid Receptor ◽

Opioid Receptors ◽

Partial Agonist ◽

Clinical Trial Data ◽

Receptor Activation ◽

Cellular Mechanisms ◽

Μ Opioid Receptor ◽

Addictive Potential

Buprenorphine’s unique pharmacologic mechanisms of action lend itself to a higher level of complexity than its typical characterization as a partial agonist at μ-opioid receptors. It is well-documented that its additional activity at Δ- and κ-opioid receptors, and opioid receptor ligand 1 may be associated with varying degrees of analgesia and usual opioid-related adverse effects. However, novel downstream molecular and cellular mechanisms from μ-opioid receptor activation contain potential new insights into its overall unique effects. These include buprenorphine’s peculiar ability to induce analgesia at escalating doses, while exhibiting a plateaued effect on respiratory depression, euphoria, gastrointestinal (GI) motility, depression, anxiety, and addictive potential. Thus, this review aims to discuss several of these emerging mechanisms to gain a better understanding of these curious actions, as well as support much of this in vitro evidence with various human clinical trial data to further support buprenorphine’s place on the analgesic ladder.

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