scholarly journals In Vitro and In Vivo Profile of PPL-101 and PPL-103: Mixed Opioid Partial Agonist Analgesics with Low Abuse Potential

2017 ◽  
Vol 8 ◽  
Author(s):  
Taline V. Khroyan ◽  
Andrea Cippitelli ◽  
Nicholas Toll ◽  
John A. Lawson ◽  
William Crossman ◽  
...  
Keyword(s):  
Partial Agonist ◽  
Abuse Potential

Effect of calcitonin on urine concentration in the rat

1983 ◽  
Vol 244 (4) ◽  
pp. F432-F435 ◽  
Author(s):  
S. Carney ◽  
T. Morgan ◽  
C. Ray ◽  
L. Thompson
Keyword(s):  
Water Permeability ◽  
Partial Agonist ◽  
Collecting Duct ◽  
Free Water ◽  
Urine Concentration ◽  
Distal Nephron ◽  
Free Water Clearance ◽  
Normal Increase

Because mammalian distal nephron segments with both calcitonin- and antidiuretic hormone- (ADH) sensitive adenylate cyclase activity have been described, in vivo and in vitro experiments were performed to study the effect of calcitonin on rat distal nephron water permeability. Calcitonin 1 and 0.1 U/ml, but not 0.01 U/ml, significantly increased the diffusional water permeability in the isolated papillary collecting duct by 15 and 11%, respectively. However, this effect was small when compared with a 68% increase with a supramaximal concentration of ADH (from 4.0 +/- 0.3 to 6.7 +/- 0.9 microns/s; n = 6, P less than 0.01). The normal increase in water permeability with increasing concentration of ADH (0.02 and 0.2 mU/ml) was depressed by the previous addition of calcitonin (1 U/ml) to the bath but was unaltered with the supramaximal ADH concentration (2 mU/ml). Verapamil, a compound that antagonizes cellular calcium entry, did not alter the effect of calcitonin on diffusional water permeability. Calcitonin in concentrations of 0.05, 0.5, and 5 U/ml produced a significant reduction in urine flow and free water clearance. Pretreatment with calcitonin in these concentrations inhibited the antidiuretic action of ADH. These studies suggest that calcitonin acts as a partial agonist to ADH within the distal nephron. It is unclear whether such an action represents a physiological or a pharmacological effect.

scholarly journals Partial agonist activity of R3(BΔ23–27)R/I5 at RXFP3 – Investigation of in vivo and in vitro pharmacology

2015 ◽  
Vol 747 ◽  
pp. 123-131 ◽  
Author(s):  
Lisbeth Kristensson ◽  
Gaëll Mayer ◽  
Karolina Ploj ◽  
Martina Wetterlund ◽  
Susanne Arlbrandt ◽  
...  
Keyword(s):  
Partial Agonist ◽  
Agonist Activity ◽  
Partial Agonist Activity ◽  
In Vitro Pharmacology

scholarly journals PPAR-gamma Fun(gi) With Prostaglandin

2020 ◽  
Vol 17 ◽  
pp. 155076291989964
Author(s):  
Robert J. Evans ◽  
Simon A. Johnston
Keyword(s):  
Partial Agonist ◽  
Ppar Gamma ◽  
Host Cells ◽  
Culture Models ◽  
Important Regulator ◽  
Inflammatory Phenotypes ◽  
First Time ◽  
Cell Culture Models

In our recent publication, we show for the first time that the fungal pathogen Cryptococcus neoformans is able to manipulate host cells by producing eicosanoids that mimic those found in the host. Using complementary in vivo zebrafish and in vitro macrophage cell culture models of Cryptococcus infection, we found that these eicosanoids manipulate host innate immune cells by activating the host receptor PPAR-gamma which is an important regulator of macrophage inflammatory phenotypes. We initially identified PGE2 as the eicosanoid species responsible for this effect; however, we later found that a derivative of PGE2—15-keto-PGE2—was ultimately responsible and that this eicosanoid acted as a partial agonist to PPAR-gamma. In this commentary, we will discuss some of the concepts and conclusions in our original publication and expand on their implications and future directions.

scholarly journals Adenosine Receptors as Neuroinflammation Modulators: Role of A1 Agonists and A2A Antagonists

Cells ◽  
2020 ◽  
Vol 9 (7) ◽  
pp. 1739
Author(s):  
Aleix Martí Navia ◽  
Diego Dal Ben ◽  
Catia Lambertucci ◽  
Andrea Spinaci ◽  
Rosaria Volpini ◽  
...  
Keyword(s):  
Partial Agonist ◽  
Pathological Condition ◽  
Neuroprotective Effect ◽  
Antioxidant Properties ◽  
Potential Candidate ◽  
In Vivo Models ◽  
Tnf Α

The pathological condition of neuroinflammation is caused by the activation of the neuroimmune cells astrocytes and microglia. The autacoid adenosine seems to be an important neuromodulator in this condition. Its main receptors involved in the neuroinflammation modulation are A1AR and A2AAR. Evidence suggests that A1AR activation produces a neuroprotective effect and A2AARs block prevents neuroinflammation. The aim of this work is to elucidate the effects of these receptors in neuroinflammation using the partial agonist 2′-dCCPA (2-chloro-N6-cyclopentyl-2′-deoxyadenosine) (C1 KiA1AR = 550 nM, KiA2AAR = 24,800 nM, and KiA3AR = 5560 nM, α = 0.70, EC50A1AR = 832 nM) and the newly synthesized in house compound 8-chloro-9-ethyl-2-phenethoxyadenine (C2 KiA2AAR = 0.75 nM; KiA1AR = 17 nM and KiA3AR = 227 nM, IC50A2AAR = 251 nM unpublished results). The experiments were performed in in vitro and in in vivo models of neuroinflammation. Results showed that C1 was able to prevent the inflammatory effect induced by cytokine cocktail (TNF-α, IL-1β, and IFN-γ) while C2 possess both anti-inflammatory and antioxidant properties, counteracting both neuroinflammation in mixed glial cells and in an animal model of neuroinflammation. In conclusion, C2 is a potential candidate for neuroinflammation therapy.

scholarly journals Assessment of select synthetic cannabinoid receptor agonist bias and selectivity between the type 1 and type 2 cannabinoid receptor

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Ayat Zagzoog ◽  
Asher L. Brandt ◽  
Tallan Black ◽  
Eunhyun D. Kim ◽  
Riley Burkart ◽  
...  
Keyword(s):  
Cannabinoid Receptors ◽  
Cannabinoid Receptor ◽  
Partial Agonist ◽  
Synthetic Cannabinoid ◽  
Receptor Subtype ◽  
Service Agency ◽  
Subtype Selectivity ◽  
Insight Into

AbstractThe first synthetic cannabinoid receptor agonists (SCRAs) were designed as tool compounds to study the endocannabinoid system’s two predominant cannabinoid receptors, CB1R and CB2R. Unfortunately, novel SCRAs now represent the most rapidly proliferating novel psychoactive substances (NPS) of abuse globally. Unlike ∆9-tetrahydrocannabinol, the CB1R and CB2R partial agonist and the intoxicating constituent of Cannabis, many SCRAs characterized to date are full agonists of CB1R. Gaining additional insight into the pharmacological activity of these SCRAs is critical to assess and regulate NPSs as they enter the marketplace. The purpose of this study was to assess select SCRAs recently identified by Canadian police, border service agency, private companies and the illicit market as potential CB1R and CB2R agonists. To this end, fifteen SCRAs were screened for in vitro activity and in silico interactions at CB1R and CB2R. Several SCRAs were identified as being highly biased for cAMP inhibition or βarrestin2 recruitment and receptor subtype selectivity between CB1R and CB2R. The indazole ring and halogen-substituted butyl or pentyl moieties were identified as two structural features that may direct βarrestin2 bias. Two highly-biased SCRAs—JWH-018 2′-napthyl-N-(3-methylbutyl) isomer (biased toward cAMP inhibition) and 4-fluoro MDMB-BINACA (biased toward βarrestin2 recruitment) displayed unique and differential in vivo activity in mice. These data provide initial insight into the correlations between structure, signalling bias, and in vivo activity of the SCRAs.

scholarly journals Mercaptoacetate blocks fatty acid-induced GLP-1 secretion in male rats by directly antagonizing GPR40 fatty acid receptors

2016 ◽  
Vol 310 (8) ◽  
pp. R724-R732 ◽  
Author(s):  
Ai-Jun Li ◽  
Qing Wang ◽  
Thu T. Dinh ◽  
Steve M. Simasko ◽  
Sue Ritter
Keyword(s):  
Fatty Acid ◽  
Partial Agonist ◽  
Male Rats ◽  
Alternative Mechanism ◽  
Nodose Ganglion Neurons ◽  
Glucagon Like Peptide 1 ◽  
Glucose Stimulated Insulin Secretion ◽  
Ganglion Neurons

Mercaptoacetate (MA) is an orexigenic agent reported to block fatty acid (FA) oxidation. Recently, however, we reported evidence from isolated nodose ganglion neurons that MA antagonizes the G protein-coupled long- and medium-chain FA receptor GPR40. GPR40 mediates FA-induced secretion of the satietogenic incretin peptide glucagon-like peptide 1 (GLP-1), by enteroendocrine L cells, as well as FA-induced enhancement of glucose-stimulated insulin secretion. Our results in cultured nodose neurons suggest that MA would also block GPR40 in enteroendocrine cells controlling GLP-1 secretion. If so, this would suggest an alternative mechanism by which MA increases food intake. We tested the hypothesis that MA blocks FA-induced GLP-1 secretion in vitro using cultured STC-1 cells (a murine enteroendocrine cell line) and in vivo in adult male rats. In vitro, MA blocked the increase in both cytosolic Ca2+ and GLP-1 release stimulated by FAs and also reduced (but less effectively) the response of STC-1 cells to grifolic acid, a partial agonist of the GPR120 FA receptor. In vivo, MA reduced GLP-1 secretion following olive oil gavage while also increasing glucose and decreasing insulin levels. The carnitine palmatoyltransferase 1 antagonist etomoxir did not alter these responses. Results indicate that MA's actions, including its orexigenic effect, are mediated by GPR40 (and possibly GPR120) receptor antagonism and not by blockade of fat oxidation, as previously believed. Analysis of MA's interaction with GPR40 may facilitate understanding of the multiple functions of this receptor and the manner in which FAs participate in the control of hunger and satiety.

scholarly journals The functional antagonist Met-RANTES: A modified agonist that induces differential CCR5 trafficking

2009 ◽  
Vol 14 (4) ◽  
Author(s):  
Debra Kiss ◽  
James Longden ◽  
Gregory Fechner ◽  
Vicky Avery
Keyword(s):  
Golgi Apparatus ◽  
Autoimmune Diseases ◽  
Chemokine Receptor ◽  
Partial Agonist ◽  
Cell Communication ◽  
Receptor Trafficking ◽  
Cell Surface Expression ◽  
Recycling Endosomes

AbstractCC chemokine receptor 5 (CCR5) is a pro-inflammatory chemokine receptor that is expressed on cells of the immune system, and specializes in cell migration in response to inflammation and tissue damage. Due to its key role in cell communication and migration, this receptor is involved in various inflammatory and autoimmune diseases, in addition to HIV infection. Met-RANTES is a modified CCR5 ligand that has previously been shown to antagonize CCR5 activation and function in response to its natural ligands in vitro. In vivo, Met-RANTES is able to reduce inflammation in models of induced inflammatory and autoimmune diseases. However, due to the fact that Met-RANTES is also capable of partial agonist activity regarding receptor signaling and internalization, it is clear that Met-RANTES does not function as a conventional receptor antagonist. To further elucidate the effect of Met-RANTES on CCR5, receptor trafficking was investigated in a CHO-CCR5-GFP cell line using the Opera confocal plate reader. The internalization response of CCR5 was quantified, and showed that Met-RANTES internalized CCR5 in a slower, less potent manner than the agonists CCL3 and CCL5. Fluorescent organelle labeling and live cell imaging showed CCL3 and CCL5 caused CCR5 to traffic through sorting endosomes, recycling endosomes and the Golgi apparatus. In contrast, Met-RANTES caused CCR5 to traffic through sorting endosomes and the Golgi apparatus in a manner that was independent of recycling endosomes. As receptor trafficking impacts on cell surface expression and the ability of the receptor to respond to more ligand, this information may indicate an alternative regulation of CCR5 by Met-RANTES that allows the modified ligand to reduce inflammation through stimulation of a pro-inflammatory receptor.

METABOLISM AND DISPOSITION OF VARENICLINE, A SELECTIVE α4β2 ACETYLCHOLINE RECEPTOR PARTIAL AGONIST, IN VIVO AND IN VITRO

2005 ◽  
Vol 34 (1) ◽  
pp. 121-130 ◽  
Author(s):  
R. Scott Obach ◽  
Anne E. Reed-Hagen ◽  
Suzanne S. Krueger ◽  
Beth J. Obach ◽  
Thomas N. O'Connell ◽  
...  
Keyword(s):  
Acetylcholine Receptor ◽  
Partial Agonist
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