Assessing the affinity of oxazolidinedione/hydantoin derivatives for the human 5HT1A/2A receptor through homology modeling and docking studies

2021 ◽  
Vol 23 (09) ◽  
pp. 46-66
Author(s):  
Meenakshi Dhanawat ◽  
◽  
Sumeet Gupta ◽  
Rina Das ◽  
Dinesh Kumar Mehta ◽  
...  
Keyword(s):  
Binding Site ◽  
Adrenergic Receptor ◽  
Homology Model ◽  
Docking Studies ◽  
Binding Affinities ◽  
Docking Algorithm ◽  
Glide Docking ◽  
Β2 Adrenergic Receptor ◽  
Hydantoin Derivatives

A flexible docking of a series of heteroaryl compounds to the binding site of a model of human 5-HT1A/2A receptor was exercised using GLIDE docking methods. The resultant docking scores were used to correlate the in vivo affinity data. The GLIDE docking algorithm when used with a homology model of 5HT1A/2A was based on β2- adrenergic receptor template. The influence of structure and hydrophobic properties of aryl moiety on binding affinities was discussed and a model for ligand binding in the hydrophobic part of the binding site was proposed.

β-blockade abolishes the augmented cardiac tPA release induced by transactivation of heterodimerised bradykinin receptor-2 and β2-adrenergic receptor in vivo

2014 ◽  
Vol 112 (11) ◽  
pp. 951-959 ◽  
Author(s):  
Morten Eriksen ◽  
Arnfinn Ilebekk ◽  
Alessandro Cataliotti ◽  
Cathrine Rein Carlson ◽  
Torstein Lyberg ◽  
...  
Keyword(s):  
Adrenergic Receptor ◽  
Sympathetic Nerves ◽  
Ventricular Myocardium ◽  
Left Ventricular ◽  
Left Ventricular Myocardium ◽  
Adrenergic Stimulation ◽  
Β2 Adrenergic Receptor ◽  
Β Blocker

SummaryBradykinin (BK) receptor-2 (B2R) and β2-adrenergic receptor (β2AR) have been shown to form heterodimers in vitro. However, in vivo proofs of the functional effects of B2R-β2AR heterodimerisation are missing. Both BK and adrenergic stimulation are known inducers of tPA release. Our goal was to demonstrate the existence of B2R-β2AR heterodimerisation in myocardium and to define its functional effect on cardiac release of tPA in vivo. We further investigated the effects of a non-selective β-blocker on this receptor interplay. To investigate functional effects of B2R-β2AR heterodimerisation (i. e. BK transactivation of β2AR) in vivo, we induced serial electrical stimulation of cardiac sympathetic nerves (SS) in normal pigs that underwent concomitant BK infusion. Both SS and BK alone induced increases in cardiac tPA release. Importantly, despite B2R desensitisation, simultaneous BK infusion and SS (BK+SS) was characterised by 2.3 ± 0.3-fold enhanced tPA release compared to SS alone. When β-blockade (propranolol) was introduced prior to BK+SS, tPA release was inhibited. A persistent B2R-β2AR heterodimer was confirmed in BK-stimulated and nonstimulated left ventricular myocardium by immunoprecipitation studies and under non-reducing gel conditions. All together, these results strongly suggest BK transactivation of β2AR leading to enhanced β2AR-mediated release of tPA. Importantly, non-selective β-blockade inhibits both SS-induced release of tPA and the functional effects of B2R-β2AR heterodimerisation in vivo, which may have important clinical implications.

scholarly journals A Specific Cholesterol Binding Site Is Established by the 2.8 Å Structure of the Human β2-Adrenergic Receptor

Structure ◽  
2008 ◽  
Vol 16 (6) ◽  
pp. 897-905 ◽  
Author(s):  
Michael A. Hanson ◽  
Vadim Cherezov ◽  
Mark T. Griffith ◽  
Christopher B. Roth ◽  
Veli-Pekka Jaakola ◽  
...  
Keyword(s):  
Binding Site ◽  
Adrenergic Receptor ◽  
Β2 Adrenergic Receptor ◽  
Cholesterol Binding

Abstract 19409: β2-Adrenergic Receptor Regulation of Innate Immune Responses Following Acute Myocardial Injury

Circulation ◽  
2015 ◽  
Vol 132 (suppl_3) ◽  
Author(s):  
Laurel A Grisanti ◽  
Anna Gumpert ◽  
Joshua Gorsky ◽  
Ashley A Repas ◽  
Erhe Gao ◽  
...  
Keyword(s):  
Immune Responses ◽  
Adrenergic Receptor ◽  
Inflammatory Responses ◽  
Critical Role ◽  
Cellular Migration ◽  
Chimeric Mouse ◽  
Ccr2 Expression ◽  
Β2 Adrenergic Receptor ◽  
The Impact

Inflammatory responses are important for cardiac remodeling and tissue repair after myocardial infarction (MI). The sympathetic nervous system is known to regulate immune responses, in large part through the β2-adrenergic receptor (β2AR), however the influence of β2AR in regulating the inflammatory response following MI is unknown. Thus, to examine the contribution of β2AR on immune cells following MI, wild-type (WT) mice were irradiated and then received β2ARKO or WT control bone marrow (BM) transplants to create immune cell-specific knockout (KO) animals. Lack of β2AR expression in BM resulted in 100% mortality from cardiac rupture within two weeks of receiving MI, in contrast to their WT counterparts that had ∼20% death. Granulocyte populations were sequestered in the spleen of β2ARKO chimeric mice resulting in reductions in post-MI infiltration of monocyte/macrophage, neutrophil and mast cell populations into the heart. Additionally, alterations in chemokine receptor levels, particularly CCR2, on BM resulted in decreased cellular migration, and use of a CCR2 antagonist in vivo recapitulated the β2ARKO chimeric mouse phenotype following MI. Administration of β2AR agonists in vitro and in vivo increased CCR2 expression and BM migration while β2AR antagonists decreased CCR2 expression and increased splenic leukocyte retention in vivo . Use of pepducins as allosteric modulators of β2AR signaling demonstrated the importance of β-arrestin-mediated signaling in increasing CCR2 expression and responses. The impact of β2AR deletion on BM cell CCR2 expression and migration, splenic retention of leukocytes and reciprocal cardiac leukocyte infiltration following MI could be reversed via lentivirus-mediated β2AR rescue in the β2ARKO BM prior to transplantation. These results demonstrate the critical role of β2AR in the regulation of CCR2 expression on hematopoietic cells and its importance in mounting an immune response to promote healing following acute cardiac injury.

Probing the Existence of a Metastable Binding Site at the β2-Adrenergic Receptor with Homobivalent Bitopic Ligands

2019 ◽  
Vol 62 (17) ◽  
pp. 7806-7839 ◽  
Author(s):  
Birgit I. Gaiser ◽  
Mia Danielsen ◽  
Emil Marcher-Rørsted ◽  
Kira Røpke Jørgensen ◽  
Tomasz M. Wróbel ◽  
...  
Keyword(s):  
Binding Site ◽  
Adrenergic Receptor ◽  
Β2 Adrenergic Receptor

scholarly journals β2-Adrenergic receptor-selective agonist clenbuterol prevents Fas-induced liver apoptosis and death in mice

1999 ◽  
Vol 276 (3) ◽  
pp. G647-G654 ◽  
Author(s):  
Claudine André ◽  
Dominique Couton ◽  
Jesintha Gaston ◽  
Loubna Erraji ◽  
Laurent Renia ◽  
...  
Keyword(s):  
Adenylyl Cyclase ◽  
Adrenergic Receptor ◽  
Rat Hepatocytes ◽  
Cell Types ◽  
Expression Level ◽  
Selective Agonist ◽  
Camp Signaling Pathway ◽  
Β2 Adrenergic Receptor ◽  
Induced Apoptosis

Stimulation of the cAMP-signaling pathway modulates apoptosis in several cell types and inhibits Jo2-mediated apoptosis in cultured rat hepatocytes. No information is yet available as to whether the hepatic β2-adrenergic receptor (AR) expression level, including β2-AR-dependent adenylyl cyclase activation, modulates hepatocyte sensitivity to apoptosis in vivo or whether this sensitivity can be modified by β2-AR ligands. We have examined this using C57BL/6 mice, in which hepatic β2-AR densities are low, and transgenic F28 mice, which overexpress β2-ARs and have elevated basal liver adenylyl cyclase activity. The F28 mice were resistant to Jo2-induced liver apoptosis and death. The β-AR antagonist propranolol sensitized the F28 livers to Jo2. In normal mice clenbuterol, a β2-AR-specific agonist, considerably reduced Jo2-induced liver apoptosis and death; salbutamol, another β2-AR-selective agonist, also reduced Jo2-induced apoptosis and retarded death but with less efficacy than clenbuterol; and propranolol blocked the protective effect of clenbuterol. This indicates that the expression level of functional β2-ARs modulates Fas-regulated liver apoptosis and that this apoptosis can be inhibited in vivo by giving β2-AR agonists. This may well form the basis for a new therapeutic approach to diseases involving abnormal apoptosis.

scholarly journals MO330ACTIVATION OF Β2 ADRENERGIC RECEPTOR SIGNALING IN MACROPHAGES BLOCKS SYSTEMIC INFLAMMATION AND PROTECTS AGAINST RENAL ISCHEMIA/REPERFUSION INJURY

2021 ◽  
Vol 36 (Supplement_1) ◽  
Author(s):  
Sho Hasegawa ◽  
Tsuyoshi Inoue ◽  
Masaomi Nangaku ◽  
Reiko Inagi
Keyword(s):  
Rna Sequencing ◽  
Systemic Inflammation ◽  
Adrenergic Receptor ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Renal Tissue ◽  
Β2 Adrenergic Receptor ◽  
Anti Inflammatory

Abstract Background and Aims The sympathetic nervous system regulates immune cell dynamics. However, the detailed role of sympathetic signaling in inflammatory diseases is still unclear because it varies according to the disease situation and responsible cell types. Here, we focused on sympathetic signaling in macrophages and sought to determine its detailed roles in lipopolysaccharide (LPS)-induced systemic inflammation and renal ischemia/reperfusion injury (IRI). Method In vitro, RAW 264.7 cells and murine peritoneal macrophages were used to determine the effects of β2 adrenergic receptor (Adrb2) signaling on LPS-induced proinflammatory cytokine (tumor necrosis factor-α; TNF-α) production. We also identified the critical gene that mediates the anti-inflammatory effect of Adrb2 signaling by RNA-sequencing. In vivo, we examined the effects of salbutamol (a selective Adrb2 agonist) in LPS-induced systemic inflammation and renal IRI. The involvement of macrophage Adrb2 signaling was confirmed by macrophage-specific Adrb2 conditional knockout (cKO) mice and adoptive transfer of salbutamol-treated macrophages. We also performed single-cell RNA sequencing of renal tissue to analyze the renoprotective role of salbutamol-treated macrophages in detail. Results In vitro, norepinephrine, a sympathetic neurotransmitter, suppressed LPS-induced TNF-α production in macrophages. This anti-inflammatory effect was also induced by salbutamol and reversed by butoxamine (a selective Adrb2 antagonist) in a dose-dependent manner, indicating the importance of Adrb2 in this process. RNA sequencing of these macrophages revealed that T-cell immunoglobulin and mucin-3 (Tim3) expressions were upregulated by the activation of Adrb2 signaling, which partially mediated the anti-inflammatory phenotypic alteration in macrophages. In vivo, salbutamol administration mitigated LPS-induced systemic inflammation and protected against renal IRI; this protection was mitigated in macrophage-specific Adrb2 cKO mice. Adoptive transfer of salbutamol-treated macrophages also protected against renal IRI (Figure 1). Single-cell RNA sequencing revealed that this protection was associated with the accumulation of Tim3-expressing macrophages in the renal tissue. Conclusion The activation of β2 adrenergic receptor signaling in macrophages induces anti-inflammatory phenotypic alterations partially via the induction of Tim3 expressions, which blocks LPS-induced systemic inflammation and protects against renal IRI.

scholarly journals Enhancement of cardiac function after adenoviral-mediated in vivo intracoronary β2-adrenergic receptor gene delivery

1999 ◽  
Vol 104 (1) ◽  
pp. 21-29 ◽  
Author(s):  
John P. Maurice ◽  
Jonathan A. Hata ◽  
Ashish S. Shah ◽  
David C. White ◽  
Patricia H. McDonald ◽  
...  
Keyword(s):  
Gene Delivery ◽  
Cardiac Function ◽  
Adrenergic Receptor ◽  
Receptor Gene ◽  
Β2 Adrenergic Receptor ◽  
Adrenergic Receptor Gene
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