The in vitro pharmacology and non-clinical cardiovascular safety studies of a novel 5-HT 4 receptor agonist, DSP-6952

The effect of γ-aminobutyric acid (GABA) on neuronal firing rate in rat suprachiasmatic nucleus (SCN) slices was examined using continuous recording methods. GABA inhibited neuronal discharge during both the subjective day and the subjective night in a concentration-dependent manner characterized by two apparent affinity states. The GABAA receptor agonist muscimol caused potent inhibition regardless of circadian time; repeated applications of the agonist did not reverse the direction of effect. The GABAA receptor antagonists bicuculline and picrotoxin increased excitability when applied during either subjective day or subjective night. A significant increase in GABAA receptor– mediated inhibition, as well as endogenous GABAergic tone, was observed on the second day after slice preparation. The GABAB receptor agonist baclofen inhibited cell firing during subjective day and night, but the GABAB antagonist phaclofen had no significant effect. These data provide additional strong support for a predominantly inhibitory role of GABA in the rat SCN, regardless of the time of application in relation to the circadian rhythm, and demonstrate an important level of plasticity of this system in vitro.

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Fused Azaindole Derivatives: Molecular Design, Synthesis and In Vitro Pharmacology Leading to the Preferential Dopamine D3 Receptor Agonist FAUC 725

Bioorganic & Medicinal Chemistry Letters ◽

10.1016/s0960-894x(02)00390-6 ◽

2002 ◽

Vol 12 (17) ◽

pp. 2377-2380 ◽

Cited By ~ 38

Author(s):

Stefan Löber ◽

Harald Hübner ◽

Peter Gmeiner

Keyword(s):

Receptor Agonist ◽

Molecular Design ◽

Dopamine D3 Receptor ◽

D3 Receptor ◽

Design Synthesis ◽

In Vitro Pharmacology ◽

Dopamine D3

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Absorption, Metabolism, and Excretion, In Vitro Pharmacology, and Clinical Pharmacokinetics of Ozanimod, a Novel Sphingosine 1-Phosphate Receptor Agonist

Drug Metabolism and Disposition ◽

10.1124/dmd.120.000220 ◽

2021 ◽

pp. DMD-AR-2020-000220

Author(s):

Sekhar Surapaneni ◽

Usha Yerramilli ◽

April Bai ◽

Deepak Dalvie ◽

Jennifer Brooks ◽

...

Keyword(s):

Receptor Agonist ◽

Clinical Pharmacokinetics ◽

Sphingosine 1 Phosphate ◽

In Vitro Pharmacology

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In vitro and in vivo safety studies indicate that R15, a synthetic poly‐arginine peptide, could safely reverse the effects of unfractionated heparin

FEBS Open Bio ◽

10.1002/2211-5463.13240 ◽

2021 ◽

Author(s):

Tong Li ◽

Zhiyun Meng ◽

Xiaoxia Zhu ◽

Hui Gan ◽

Ruolan Gu ◽

...

Keyword(s):

Unfractionated Heparin ◽

Safety Studies

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The Diameter of Retinal Arterioles Is Unaffected by Intravascular Administration of the Adenosine A2A Receptor Agonist Regadenoson in Normal Persons

Biomedicine Hub ◽

10.1159/000500563 ◽

2019 ◽

Vol 4 (2) ◽

pp. 1-10 ◽

Cited By ~ 1

Author(s):

Anna Dons-Jensen ◽

Line Petersen ◽

Hans-Erik Bøtker ◽

Toke Bek

Keyword(s):

Intravenous Administration ◽

Receptor Agonist ◽

Adenosine A2a Receptor ◽

Retinal Vessels ◽

Adenosine Receptor Agonists ◽

Retinal Arterioles ◽

A2a Receptor ◽

Adenosine A2a

Background: The neurotransmitter adenosine has been proposed to be involved in the pathogenesis of diabetic retinopathy, which may be due to the vasoactive properties of the compound. Previous studies have shown that adenosine can affect the tone of retinal arterioles in vitro to induce dilatation mediated by A2A and A2Breceptors and constriction mediated by A1 and A3 receptors. Purpose: To investigate effects of intravenous administration of the adenosine A2A receptor agonist regadenoson on the diameter of retinal vessels in vivo. Method: The diameter responses of larger retinal arterioles and venules were evaluated using the dynamic vessel analyser in 20 normal persons (age 22–31 years) after intravenous administration of the adenosine A2A receptor agonist regadenoson during exposure to systemic normoxia and hypoxia. Results: The diameter of retinal arterioles and venules increased significantly during stimulation with flickering light (p < 0.0001). Regadenoson reduced the flicker-induced dilatation of venules during normoxia (p = 0.0006), but otherwise had no effect on vessel diameters (p > 0.08 for all comparisons). Conclusions:Intravenous administration of the adenosine A2A receptor agonist regadenoson had no significant effect on the diameter of retinal arterioles. Future studies should investigate differential effects of intra- and extravascular administration of adenosine receptor agonists on retinal vessels.

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Adhesion G Protein–Coupled Receptors: From In Vitro Pharmacology to In Vivo Mechanisms

Molecular Pharmacology ◽

10.1124/mol.115.098749 ◽

2015 ◽

Vol 88 (3) ◽

pp. 617-623 ◽

Cited By ~ 30

Author(s):

Kelly R. Monk ◽

Jörg Hamann ◽

Tobias Langenhan ◽

Saskia Nijmeijer ◽

Torsten Schöneberg ◽

...

Keyword(s):

G Protein ◽

G Protein Coupled Receptors ◽

In Vitro Pharmacology ◽

G Protein Coupled

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Further pharmacological evaluation of a novel synthetic peptide bradykinin B2 receptor agonist

Biological Chemistry ◽

10.1515/hsz-2012-0295 ◽

2013 ◽

Vol 394 (3) ◽

pp. 353-360 ◽

Cited By ~ 9

Author(s):

Martin Savard ◽

Julie Labonté ◽

Céléna Dubuc ◽

Witold Neugebauer ◽

Pedro D’Orléans-Juste ◽

...

Keyword(s):

Knockout Mice ◽

Synthetic Peptide ◽

Receptor Agonist ◽

Rabbit Lung ◽

Hypotensive Action ◽

Duration Of Action ◽

Selective Agonist ◽

Comparable Magnitude

Abstract We recently identified a novel human B2 receptor (B2R) agonist [Hyp3,Thi5,NChg7,Thi8]-bradykinin (NG291) with greater in vitro and in vivo potency and duration of action than natural bradykinin (BK). Here, we further examined its stability and selectivity toward B2R. The hypotensive, antithrombotic, and profibrinolytic functions of NG291 relative to BK and its analogue ([Hyp3,Thi5,(4-Me)Tyr8(ΨCH2NH)Arg9]-BK) (RMP-7) were also tested. Contraction assays using isolated mouse stomachs (containing kinin B1R, B2R, and kininase I- and II-like activities) showed that NG291 is a more potent contractant than BK and is inhibited by HOE-140 (B2R antagonist) but unaffected by R954 (B1R antagonist), whereas both decreased the potency of BK. In stomach tissues from B2R knockout mice, BK maintained its activity via B1R, whereas NG291 had no contractile effect, indicating that it was selective for B2R. Unlike BK, NG291 was not degraded by rabbit lung ACE. Comparing intravenously administered BK and NG291 revealed that NG291 exhibited more potent and prolonged hypotensive action and greater antithrombotic and profibrinolytic activities. These effects were of comparable magnitude to RMP-7 and were absent in B2R knockout mice. We concluded that NG291 is a novel biostable B2R-selective agonist that may prove suitable for investigating the (pre)clinical cardioprotective efficacy of B2R activation.

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