Related Experiment Video

Updated: Jul 15, 2026

Drug-induced Sensitization of Adenylyl Cyclase: Assay Streamlining and Miniaturization for Small Molecule and siRNA Screening Applications
09:39

Drug-induced Sensitization of Adenylyl Cyclase: Assay Streamlining and Miniaturization for Small Molecule and siRNA Screening Applications

Published on: January 27, 2014

Screening the Tox21 Compound Library for Chemicals That Stimulate the Adrenergic β1 Receptor

Precious A Adesina1, Li Zhang1, Chainarong Sukhawanit1

  • 1Division of Preclinical Innovation, National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, Maryland20892, United States.

Chemical Research in Toxicology
|July 14, 2026
PubMed

Insights

Environmental chemicals can impact heart function by modulating beta-1 adrenergic receptors (ADRβ1). Quantitative high-throughput screening identified new ADRβ1 agonists, expanding knowledge of cardiovascular signaling chemicals.

Area of Science:

  • Environmental health
  • Cardiovascular toxicology
  • Pharmacology

Background:

  • Beta-1 adrenergic receptors (ADRβ1) are key regulators of cardiac function.
  • The impact of environmental chemicals on ADRβ1 is not well understood, posing potential risks to cardiovascular health.

Purpose of the Study:

  • To identify ADRβ1 agonists from a large library of environmental chemicals using quantitative high-throughput screening (qHTS).
  • To evaluate the subtype selectivity and cardiotoxicity potential of identified compounds.

Main Methods:

  • Utilized a quantitative high-throughput screening (qHTS) approach with an HTRF-based cAMP assay.
  • Screened 8,947 compounds from the Tox21 10K library against ADRβ1-overexpressing HEK293 cells.
  • Assessed selectivity for ADRβ2 and ADRβ3, and inhibition of hERG channels for cardiotoxicity assessment.

Main Results:

  • Identified 118 potential ADRβ1 agonists, with 94 confirmed.
  • Validated the assay by identifying known agonists like isoproterenol and dobutamine.
  • Discovered novel ADRβ1 modulators, including GR 103691 and N,N'-dibenzylethane-1,2-diamine, some with subtype selectivity and low hERG inhibition.

Conclusions:

  • qHTS is effective for identifying environmental chemicals that modulate ADRβ1.
  • Expanded the known catalog of ADRβ1 modulators, including compounds with potential cardiovascular implications.
  • Highlighted the importance of evaluating environmental chemicals for their effects on cardiovascular signaling pathways.

More Related Videos

Identification of Mediators of T-cell Receptor Signaling via the Screening of Chemical Inhibitor Libraries08:49

Identification of Mediators of T-cell Receptor Signaling via the Screening of Chemical Inhibitor Libraries

Published on: January 22, 2019

High Content Screening Analysis to Evaluate the Toxicological Effects of Harmful and Potentially Harmful Constituents (HPHC)11:38

High Content Screening Analysis to Evaluate the Toxicological Effects of Harmful and Potentially Harmful Constituents (HPHC)

Published on: May 10, 2016

Related Concept Videos

Adrenergic Antagonists: Chemistry and Classification of β-Receptor Blockers01:25

Adrenergic Antagonists: Chemistry and Classification of β-Receptor Blockers

β-adrenergic antagonists, or β-blockers, modulate the sympathetic nervous system by targeting β-adrenoceptors and inhibiting catecholamine-mediated sympathetic responses. β-blockers differ in their adrenoceptor subtype affinity, lipophilicity, and α-blocking capabilities. The history of β-blocker development began with the prototype, dichloroisoprenaline, which exhibited partial agonist activity. As a result, propranolol was developed as a pure antagonist but nonselective agent, paving the way...
Adrenergic Receptors: β Subtype01:26

Adrenergic Receptors: β Subtype

β-adrenoceptors have varied sensitivities towards adrenaline, noradrenaline, and isoprenaline. The order of agonist potency is as follows:
Isoprenaline > Adrenaline > Noradrenaline
Neurotransmitter binding to these receptors causes activation of adenylyl cyclase resulting in increased concentrations of cAMP and modulation of calcium ion channels within the cell. They are further classified into β1, β2, and β3 subtypes.
β1-adrenoceptors: β1-adrenoceptors have equal affinities for...
Adrenergic Antagonists: Chemistry and Classification of ɑ-Receptor Blockers01:17

Adrenergic Antagonists: Chemistry and Classification of ɑ-Receptor Blockers

Adrenergic antagonists, or sympatholytics, inhibit adrenoceptor activation driven by catecholamines or agonists. Based on their adrenoceptor specificity, adrenergic blockers can be categorized into two primary groups: α-adrenergic blockers (α-blockers) and β-adrenergic blockers (β-blockers). α-blockers interact with α1 and α2 subtypes of α-adrenoceptors.
Nonselective α-blockers: Nonselective α-blockers contain haloalkylamine or imidazoline moieties. Phenoxybenzamine, with a haloalkylamine...
Adrenergic Agonists: Direct-Acting Agents01:30

Adrenergic Agonists: Direct-Acting Agents

Drugs that mimic the action of endogenous catecholamines like noradrenaline and adrenaline are called adrenergic agonists or sympathomimetics. Based on their mechanism of action, sympathomimetics can be classified as direct-, indirect-, or mixed-acting sympathomimetics. Direct-acting adrenergic agonists activate adrenoceptors without affecting presynaptic neurons, making them independent of neuronal catecholamine-depleting agents like reserpine and guanethidine.
These agents can be classified...
Adrenergic Antagonists: Pharmacological Actions of β-Receptor Blockers01:27

Adrenergic Antagonists: Pharmacological Actions of β-Receptor Blockers

β-receptor blockers significantly impact the cardiovascular system by counteracting catecholamine-induced sympathetic responses. These medications decrease heart rate, contractility, and cardiac output, potentially leading to cardiac depression, life-threatening bradycardia, and death. Therapeutically, β-blockers function as mild antihypertensives and are utilized in treating angina pectoris and cardiac arrhythmias. However, nonselective β-blockers inhibit β2-receptors in bronchial smooth...
Adrenergic Receptors: ɑ Subtype01:31

Adrenergic Receptors: ɑ Subtype

Adrenoceptors are classified into α and ꞵ classes based on their potencies to catecholamine agonists. α-adrenoceptors show the following order of catecholamine potency:
Adrenaline ≥ Noradrenaline >> Isoprenaline
α-adrenoceptors are further divided into α1 and α2-adrenoceptors.
α1-Adrenoceptors: These receptors are located postsynaptically on the effector organs and cause constriction of smooth muscle mediated by activation of phospholipase C—inositol-1,4,5-trisphosphate...