Evolution of β-blockers: from anti-anginal drugs to ligand-directed signalling

Baker, Jillian G.; Hill, Stephen J.; Summers, Roger J.

doi:10.1016/j.tips.2011.02.010

Cited by 115 publications

(92 citation statements)

References 118 publications

(100 reference statements)

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“…Hypertension, chronic stable angina, IHD, postmyocardial infaction (Helfand et al, 2007;Ram, 2010;Baker et al, 2011) Betaxolol 7.38 (Baker, 2005) NT Selective…”

Section: Resultsmentioning

confidence: 99%

“…Hypertension, glaucoma (Helfand et al, 2007;Ram, 2010;Baker et al, 2011) Bisoprolol 5.94-6.70 (Del Carmine et al, 2002;Hoffmann et al, 2004;Baker, 2005) ↓ 6.51-6.70 (Baker et al, 2003;Galandrin and Bouvier, 2006) Selective…”

Section: Resultsmentioning

confidence: 99%

“…Hypertension, angina, IHD, heart failure (Helfand et al, 2007;Baker et al, 2011) Bucindolol 8.92 (Ponicke et al, 2002Baker, 2010) ↑ 9.40 (Baker, 2010) Nonselective bAR antagonist Heart failure (Pauwels et al, 1991) .5.00 (Galandrin and Bouvier, 2006) Carvedilol 9.02-9.40 (Ponicke et al, 2002;Hoffmann et al, 2004;Baker, 2005) ↑ 9.10 (Baker et al, 2003) a 1 AR and bAR antagonist Hypertension, IHD, heart failure, post-MI (Helfand et al, 2007;Ram, 2010;Baker et al, 2011) .5.00 (Galandrin and Bouvier, 2006) (2)-Epinephrine 5.99-6.54 (Frielle et al, 1988;Del Carmine et al, 2002;Hoffmann et al, 2004;Baker, 2010) ↑ 7.74-8.22 (Liapakis et al, 2004;Elster et al, 2007;Baker, 2010) Nonselective endogenous aAR and bAR agonist Allergic reactions, asthma, cardiac failure, hemorrhage, shock (McLeanTooke et al, 2003)…”

Section: Resultsmentioning

confidence: 99%

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Quantification of Ligand Bias for Clinically Relevant β₂-Adrenergic Receptor Ligands: Implications for Drug Taxonomy

et al. 2013

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The concepts of functional selectivity and ligand bias are becoming increasingly appreciated in modern drug discovery programs, necessitating more informed approaches to compound classification and, ultimately, therapeutic candidate selection. Using the b2-adrenergic receptor as a model, we present a proof of concept study that assessed the bias of 19 b-adrenergic ligands, including many clinically used compounds, across four pathways [cAMP production, extracellular signal-regulated kinase 1/2 (ERK1/2) activation, calcium mobilization, and receptor endocytosis] in the same cell background (human embryonic kidney 293S cells). Efficacy-based clustering placed the ligands into five distinct groups with respect to signaling signatures. In some cases, apparent functional selectivity originated from offtarget effects on other endogenously expressed adrenergic receptors, highlighting the importance of thoroughly assessing selectivity of the responses before concluding receptor-specific ligand-biased signaling. Eliminating the nonselective compounds did not change the clustering of the 10 remaining compounds. Some ligands exhibited large differences in potency for the different pathways, suggesting that the nature of the receptoreffector complexes influences the relative affinity of the compounds for specific receptor conformations. Calculation of relative effectiveness (within pathway) and bias factors (between pathways) for each of the compounds, using an operational model of agonism, revealed a global signaling signature for all of the compounds relative to isoproterenol. Most compounds were biased toward ERK1/2 activation over the other pathways, consistent with the notion that many proximal effectors converge on this pathway. Overall, we demonstrate a higher level of ligand texture than previously anticipated, opening perspectives for the establishment of pluridimensional correlations between signaling profiles, drug classification, therapeutic efficacy, and safety.

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“…Hypertension, chronic stable angina, IHD, postmyocardial infaction (Helfand et al, 2007;Ram, 2010;Baker et al, 2011) Betaxolol 7.38 (Baker, 2005) NT Selective…”

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

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Quantification of Ligand Bias for Clinically Relevant β₂-Adrenergic Receptor Ligands: Implications for Drug Taxonomy

et al. 2013

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“…Nadolol is recommended for the treatment of hypertension, coronary disease and arrhythmia, moreover, according to recent studies it is also effective in the treatment of migraine and it can be safely applied against the above conditions even in the patients suffering from chronic mild asthma (Baker et al 2011;Lopez-Sendon et al 2004;Hanania et al 2010). …”

Section: Introductionmentioning

confidence: 99%

Radiodegradation of nadolol in the solid state and identification of its radiolysis products by UHPLC–MS method

et al. 2017

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Nadolol ((2R*,3S*)-5-{[(2R*)-3-(tert-butylamino)-2-hydroxypropyl]oxy}-1,2,3,4 tetrahydronaphthalene-2,3-diol) in substantia was exposed to ionizing radiation generated by a beam of high-energy electrons in an accelerator, in the standard sterilisation dose of 25 kGy and in higher doses of 50 -400 kGy. The irradiated and non-irradiated (control) samples were analysed by the infrared spectrophotometry, electron paramagnetic resonance, differential scanning calorimetry (DSC) and ultrahigh performance liquid chromatography coupled with mass spectrometry (UHPLC-MS). The irradiated samples were found to contain free radicals in concentrations much higher than that observed for the other irradiated b-blockers. On the basis of UHPLC-MS results, it was possible to establish structures of 11 compounds of the impurities and/ or products of nadolol decomposition. The main product of radiodegradation was concluded to be formed as a result of abstraction of the hydroxyl group and aromatization of the tetrahydronaphthalene ring. The results of DSC measurements confirmed the presence of radiolysis products in the irradiated samples of nadolol. A shift of the endothermic peak corresponding to melting towards lower temperatures (by 4.4°C at the dose of 400 kGy) was directly proportional to the doses of radiation used, which permits concluding that this method is sensitive and suitable for evaluation of radiodegradation of nadolol in solid phase.

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“…A diverse set of ligands for the ␤ 2 AR have also been developed that are now mainstays in the clinic (9 -13). ␤-Antagonists have been used extensively in the treatment of hypertension, and some inverse agonists such as carvedilol have been used in the treatment of congestive heart failure (11,13). ␤ 2 AR agonists, including salbutamol and formoterol, are com-monly prescribed drugs for the treatment of asthma and chronic obstructive pulmonary disease (9,12).…”

mentioning

confidence: 99%

Development and Characterization of Pepducins as Gs-biased Allosteric Agonists*

Carr

Quoyer

et al. 2014

Journal of Biological Chemistry

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Background: A G s -biased agonist for the ␤ 2 -adrenergic receptor (␤ 2 AR) has yet to be reported. Results: A screen of ␤ 2 AR pepducins identified receptor-dependent and receptor-independent pepducins that selectively activate G s . Conclusion: Receptor-dependent pepducins promote a G s -biased conformation of the ␤ 2 AR, whereas receptor-independent pepducins directly activate G s . Significance: G s -biased pepducins provide a valuable tool for the continued study of ␤ 2 AR function and may prove useful as next-generation asthma therapeutics.

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Evolution of β-blockers: from anti-anginal drugs to ligand-directed signalling

Cited by 115 publications

References 118 publications

Quantification of Ligand Bias for Clinically Relevant β₂-Adrenergic Receptor Ligands: Implications for Drug Taxonomy

Quantification of Ligand Bias for Clinically Relevant β₂-Adrenergic Receptor Ligands: Implications for Drug Taxonomy

Radiodegradation of nadolol in the solid state and identification of its radiolysis products by UHPLC–MS method

Development and Characterization of Pepducins as Gs-biased Allosteric Agonists*

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Evolution of β-blockers: from anti-anginal drugs to ligand-directed signalling

Cited by 115 publications

References 118 publications

Quantification of Ligand Bias for Clinically Relevant β2-Adrenergic Receptor Ligands: Implications for Drug Taxonomy

Quantification of Ligand Bias for Clinically Relevant β2-Adrenergic Receptor Ligands: Implications for Drug Taxonomy

Radiodegradation of nadolol in the solid state and identification of its radiolysis products by UHPLC–MS method

Development and Characterization of Pepducins as Gs-biased Allosteric Agonists*

Contact Info

Product

Resources

About

Quantification of Ligand Bias for Clinically Relevant β₂-Adrenergic Receptor Ligands: Implications for Drug Taxonomy

Quantification of Ligand Bias for Clinically Relevant β₂-Adrenergic Receptor Ligands: Implications for Drug Taxonomy