Selective 5-HT1A receptor agonists biased to pERK1/2 or β-arrestin activation show differential in vivo behavioral profiles

2018 ◽  
Author(s):  
Daria Wilczyńska ◽  
Magdalena Jastrzębska-Więsek
Keyword(s):  
Behavioral Profiles ◽  
Receptor Agonists

Selective 5-HT1A receptor agonists biased to pERK1/2 or β-arrestin activation show differential in vivo behavioral profiles

2019 ◽  
Vol 29 ◽  
pp. S423
Author(s):  
D. Wilczyńska ◽  
M. Jastrzębska-Więsek ◽  
A. Partyka ◽  
J. Śniecikowska ◽  
A. Wesołowska ◽  
...  
Keyword(s):  
Behavioral Profiles ◽  
Receptor Agonists

scholarly journals 6,5-Fused Ring, C2-Salvinorin Ester, Dual Kappa and Mu Opioid Receptor Agonists as Analgesics Devoid of Anxiogenic Effects

2021 ◽  
Author(s):  
Nicholas S. Akins ◽  
Nisha Mishra ◽  
Hannah M. Harris ◽  
Narendar Dudhipala ◽  
Seong Jong Kim ◽  
...  
Keyword(s):  
Opioid Receptor ◽  
Opioid Receptors ◽  
Analgesic Activity ◽  
Mu Opioid Receptor ◽  
Kappa Opioid Receptor ◽  
Mu Opioid ◽  
Receptor Agonists ◽  
Opioid Receptor Agonists

Analgesia is commonly mediated through the mu or kappa opioid receptor agonism. Unfortunately, selective mu or kappa receptor agonists often cause harmful side effects. Recently, ligands exhibiting dual agonism to the opioid receptors, such as to mu and kappa, or to mu and delta, have been suggested to temper undesirable adverse effects while retaining analgesic activity. Herein we report an introduction of various 6,5-fused rings to C2 of the salvinorin scaffold <i>via</i> an ester linker. <i>In vitro</i> studies showed that some of these compounds have dual agonism on kappa and mu opioid receptors, while some have triple agonism on kappa, mu, and delta. <i>In vivo </i>studies on the lead dual kappa and mu opioid receptor agonist, compound <b>10</b>, showed that it<b> </b>produced analgesic activity while avoiding anxiogenic effects in murine models, thus providing further strong evidence for the therapeutic advantages of dual opioid receptor agonists over selective opioid receptor agonists.

scholarly journals From Theory to Clinical Practice in the Use of GLP-1 Receptor Agonists and DPP-4 Inhibitors Therapy

2011 ◽  
Vol 2011 ◽  
pp. 1-8 ◽  
Author(s):  
Ilaria Dicembrini ◽  
Laura Pala ◽  
Carlo Maria Rotella
Keyword(s):  
Cell Function ◽  
Lifestyle Modification ◽  
Cell Mass ◽  
Beta Cell Mass ◽  
Minimal Risk ◽  
Dipeptidyl Peptidase 4 ◽  
Receptor Agonists ◽  
Dipeptidyl Peptidase 4 Inhibitors

Promoting long-term adherence to lifestyle modification and choice of antidiabetic agent with low hypoglycemia risk profile and positive weight profile could be the most effective strategy in achieving sustained glycemic control and in reducing comorbidities. From this perspective, vast interest has been generated by glucagon-like peptide-1 (GLP-1) receptor agonists and dipeptidyl peptidase-4 inhibitors (DPP-4i). In this review our ten-year clinical and laboratory experience byin vitroandin vivostudies is reported. Herein, we reviewed available data on the efficacy and safety profile of GLP-1 receptor agonists and DPP-4i. The introduction of incretin hormone-based therapies represents a novel therapeutic strategy, because these drugs not only improve glycemia with minimal risk of hypoglycemia but also have other extraglycemic beneficial effects. In clinical studies, both GLP-1 receptor agonists and DPP-4i, improveβcell function indexes. All these agents showed trophic effects on beta-cell mass in animal studies. The use of these drugs is associated with positive or neucral effect on body weight and improvements in blood pressure, diabetic dyslipidemia, hepatic steazosis markets, and myocardial function. These effects have the potential to reduce the burden of cardiovascular disease, which is a major cause of mortality in patients with diabetes.

Glucagon-like Peptide 1 Receptor Agonists, Diabetic Retinopathy and Angiogenesis: The AngioSafe Type 2 Diabetes Study

2019 ◽  
Vol 105 (4) ◽  
pp. e1549-e1560 ◽  
Author(s):  
Bénédicte Gaborit ◽  
Jean-Baptiste Julla ◽  
Samaher Besbes ◽  
Matthieu Proust ◽  
Clara Vincentelli ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Diabetic Retinopathy ◽  
Fundus Photography ◽  
Endothelial Cell Proliferation ◽  
Receptor Agonists ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1

Abstract Aims Recent trials provide conflicting results on the association between glucagon-like peptide 1 receptor agonists (GLP-1RA) and diabetic retinopathy (DR). The aim of the AngioSafe type 2 diabetes (T2D) study was to determine the role of GLP-1RA in angiogenesis using clinical and preclinical models. Methods We performed two studies in humans. In study 1, we investigated the effect of GLP-1RA exposure from T2D diagnosis on the severity of DR, as diagnosed with retinal imaging (fundus photography). In study 2, a randomized 4-week trial, we assessed the effect of liraglutide on circulating hematopoietic progenitor cells (HPCs), and angio-miRNAs. We then studied the experimental effect of Exendin-4, on key steps of angiogenesis: in vitro on human endothelial cell proliferation, survival and three-dimensional vascular morphogenesis; and in vivo on ischemia-induced neovascularization of the retina in mice. Results In the cohort of 3154 T2D patients, 10% displayed severe DR. In multivariate analysis, sex, disease duration, glycated hemoglobin (HbA1c), micro- and macroangiopathy, insulin therapy and hypertension remained strongly associated with severe DR, while no association was found with GLP-1RA exposure (o 1.139 [0.800–1.622], P = .47). We further showed no effect of liraglutide on HPCs, and angio-miRNAs. In vitro, we demonstrated that exendin-4 had no effect on proliferation and survival of human endothelial cells, no effect on total length and number of capillaries. Finally, in vivo, we showed that exendin-4 did not exert any negative effect on retinal neovascularization. Conclusions The AngioSafe T2D studies provide experimental and clinical data confirming no effect of GLP-1RA on angiogenesis and no association between GLP-1 exposure and severe DR.

Renal effects of selective adenosine receptor agonists in anesthetized rats

1987 ◽  
Vol 252 (2) ◽  
pp. F299-F303 ◽  
Author(s):  
P. C. Churchill ◽  
A. Bidani
Keyword(s):  
Blood Pressure ◽  
Arterial Blood Pressure ◽  
Adenosine Receptor ◽  
Renin Secretion ◽  
Renal Effects ◽  
Adenosine Receptor Agonists ◽  
Receptor Agonists ◽  
Arterial Blood ◽  
Selective Agonist

Exogenous adenosine affects renal hemodynamics, renal tubular transport processes, and the secretion of renin. However, adenosine is not a selective agonist; it activates both A1 and A2 cell-surface receptors and it binds to an intracellular P-site that inhibits adenylate cyclase activity. Recent in vitro studies have suggested that activation of A1- and A2- adenosine receptors results in opposite effects on renin secretion. The purpose of these experiments was to examine the renal effects of A1- and A2-adenosine receptor agonists in vivo. 5'-N-ethylcarboxamide adenosine (NECA), 2-chloroadenosine (2-CLA), and N6-cyclohexyladenosine (CHA) were infused intravenously at rates that produced comparable decreases in systemic arterial blood pressure. All three of these adenosine analogues produced comparable decreases in para-aminohippurate (PAH) and inulin clearances and in Na and K excretion rates. CHA, an A1-selective agonist, markedly decreased plasma renin concentration (PRC), whereas NECA, an A2-selective agonist, markedly increased PRC; 2-CLA, a nonselective agonist, produced a smaller increase in PRC. Taken together, these results suggest that occupation of A1- and A2-receptors inhibits and stimulates renin secretion in vivo, independently of the effects of these adenosine receptor agonists on arterial blood pressure, renal hemodynamics, and tubular Na and K transport.

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