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The Isoleucine at Position 118 in Transmembrane 2 Is Responsible for the Selectivity of Xamoterol, Nebivolol, and ICI89406 for the Human β1-Adrenoceptor (2023)
Journal Article
Lim, V. J. Y., Proudman, R. G. W., Monteleone, S., Kolb, P., & Baker, J. G. (2023). The Isoleucine at Position 118 in Transmembrane 2 Is Responsible for the Selectivity of Xamoterol, Nebivolol, and ICI89406 for the Human β1-Adrenoceptor. Molecular Pharmacology, 103(2), 89-99. https://doi.org/10.1124/molpharm.122.000583

Known off-target interactions frequently cause predictable drug side-effects (e.g., β1-antagonists used for heart disease, risk β2-mediated bronchospasm). Computer-aided drug design would improve if the structural basis of existing drug selectivity w... Read More about The Isoleucine at Position 118 in Transmembrane 2 Is Responsible for the Selectivity of Xamoterol, Nebivolol, and ICI89406 for the Human β1-Adrenoceptor.

Rational design, synthesis, and pharmacological evaluation of a cohort of novel beta-adrenergic receptors ligands enables an assessment of structure-activity relationships (2022)
Journal Article
Tricomi, J., Landini, L., Nieddu, V., Cavallaro, U., Baker, J., Papakyriakou, A., & Richichi, B. (2023). Rational design, synthesis, and pharmacological evaluation of a cohort of novel beta-adrenergic receptors ligands enables an assessment of structure-activity relationships. European Journal of Medicinal Chemistry, 246, Article 114961. https://doi.org/10.1016/j.ejmech.2022.114961

Biomedical applications of molecules that are able to modulate β-adrenergic signaling have become increasingly attractive over the last decade, revealing that β-adrenergic receptors (β-ARs) are key targets for a plethora of therapeutic interventions,... Read More about Rational design, synthesis, and pharmacological evaluation of a cohort of novel beta-adrenergic receptors ligands enables an assessment of structure-activity relationships.

The signaling and selectivity of α-adrenoceptor agonists for the human α2A, α2B and α2C-adrenoceptors and comparison with human α1 and β-adrenoceptors (2022)
Journal Article
Proudman, R. G. W., Akinaga, J., & Baker, J. G. (2022). The signaling and selectivity of α-adrenoceptor agonists for the human α2A, α2B and α2C-adrenoceptors and comparison with human α1 and β-adrenoceptors. Pharmacology Research and Perspectives, 10(5), Article e01003. https://doi.org/10.1002/prp2.1003

α2-adrenoceptors, (α2A, α2B and α2C-subtypes), are Gi-coupled receptors. Central activation of brain α2A and α2C-adrenoceptors is the main site for α2-agonist mediated clinical responses in hypertension, ADHD, muscle spasm and ITU management of sedat... Read More about The signaling and selectivity of α-adrenoceptor agonists for the human α2A, α2B and α2C-adrenoceptors and comparison with human α1 and β-adrenoceptors.

The affinity and selectivity of α-adrenoceptor antagonists, antidepressants and antipsychotics for the human α2A, α2B, and α2C-adrenoceptors and comparison with human α1 and β-adrenoceptors (2022)
Journal Article
Proudman, R. G. W., Akinaga, J., & Baker, J. G. (2022). The affinity and selectivity of α-adrenoceptor antagonists, antidepressants and antipsychotics for the human α2A, α2B, and α2C-adrenoceptors and comparison with human α1 and β-adrenoceptors. Pharmacology Research and Perspectives, 10(2), Article e00936. https://doi.org/10.1002/prp2.936

α2-Adrenoceptors, subdivided into α2A, α2B, and α2C subtypes and expressed in heart, blood vessels, kidney, platelets and brain, are important for blood pressure, sedation, analgesia, and platelet aggregation. Brain α2C-adrenoceptor blockade has also... Read More about The affinity and selectivity of α-adrenoceptor antagonists, antidepressants and antipsychotics for the human α2A, α2B, and α2C-adrenoceptors and comparison with human α1 and β-adrenoceptors.

The selectivity of α‐adrenoceptor agonists for the human α1A, α1B, and α1D‐adrenoceptors (2021)
Journal Article
Proudman, R. G. W., & Baker, J. G. (2021). The selectivity of α‐adrenoceptor agonists for the human α1A, α1B, and α1D‐adrenoceptors. Pharmacology Research and Perspectives, 9(4), Article e00799. https://doi.org/10.1002/prp2.799

Highly selective drugs offer a way to minimize side-effects. For agonist ligands, this could be through highly selective affinity or highly selective efficacy, but this requires careful measurements of intrinsic efficacy. The α1-adrenoceptors are imp... Read More about The selectivity of α‐adrenoceptor agonists for the human α1A, α1B, and α1D‐adrenoceptors.

Carvedilol blocks neural regulation of breast cancer progression in vivo and is associated with reduced breast cancer mortality in patients (2021)
Journal Article
Gillis, R. D., Botteri, E., Chang, A., Ziegler, A. I., Chung, N. C., Pon, C. K., …Sloan, E. K. (2021). Carvedilol blocks neural regulation of breast cancer progression in vivo and is associated with reduced breast cancer mortality in patients. European Journal of Cancer, 147, 106-116. https://doi.org/10.1016/j.ejca.2021.01.029

© 2021 Elsevier Ltd Purpose: The sympathetic nervous system drives breast cancer progression through β-adrenergic receptor signalling. This discovery has led to the consideration of cardiac β-blocker drugs as novel strategies for anticancer therapi... Read More about Carvedilol blocks neural regulation of breast cancer progression in vivo and is associated with reduced breast cancer mortality in patients.

Structure-Based Discovery of Novel Ligands for the Orexin 2 Receptor (2020)
Journal Article
Gunera, J., Baker, J. G., van Hilten, N., Rosenbaum, D. M., & Kolb, P. (2020). Structure-Based Discovery of Novel Ligands for the Orexin 2 Receptor. Journal of Medicinal Chemistry, 63(19), 11045-11053. https://doi.org/10.1021/acs.jmedchem.0c00964

The orexin receptors are peptide-sensing G protein-coupled receptors that are intimately linked with regulation of the sleep/wake cycle. We used a recently solved X-ray structure of the orexin receptor subtype 2 in computational docking calculations... Read More about Structure-Based Discovery of Novel Ligands for the Orexin 2 Receptor.

Using Esterase Selectivity to Determine the in Vivo Duration of Systemic Availability and Abolish Systemic Side Effects of Topical ?-Blockers (2020)
Journal Article
Baker, J. G., Fromont, C., Bruder, M., Thompson, K. S., Kellam, B., Hill, S. J., …Fischer, P. M. (2020). Using Esterase Selectivity to Determine the in Vivo Duration of Systemic Availability and Abolish Systemic Side Effects of Topical β-Blockers. ACS Pharmacology & Translational Science, 3(4), 737-748. https://doi.org/10.1021/acsptsci.0c00051

© 2020 American Chemical Society. For disorders of the skin, eyes, ears, and respiratory tract, topical drugs, delivered directly to the target organ, are a therapeutic option. Compared with systemic oral therapy, the benefits of topical treatments i... Read More about Using Esterase Selectivity to Determine the in Vivo Duration of Systemic Availability and Abolish Systemic Side Effects of Topical ?-Blockers.

The affinity and selectivity of ?-adrenoceptor antagonists, antidepressants, and antipsychotics for the human ?1A, ?1B, and ?1D-adrenoceptors (2020)
Journal Article
Proudman, R. G. W., Pupo, A. S., & Baker, J. G. (2020). The affinity and selectivity of ?-adrenoceptor antagonists, antidepressants, and antipsychotics for the human ?1A, ?1B, and ?1D-adrenoceptors. Pharmacology Research and Perspectives, 8(4), https://doi.org/10.1002/prp2.602

© 2020 The Authors. Pharmacology Research & Perspectives published by John Wiley & Sons Ltd, British Pharmacological Society and American Society for Pharmacology and Experimental Therapeutics. α1-adrenoceptor antagonists are widely used for hype... Read More about The affinity and selectivity of ?-adrenoceptor antagonists, antidepressants, and antipsychotics for the human ?1A, ?1B, and ?1D-adrenoceptors.

Case for continuing community NIV and CPAP during the COVID-19 epidemic (2020)
Journal Article
Baker, J. G., & Sovani, M. P. (2020). Case for continuing community NIV and CPAP during the COVID-19 epidemic. Thorax, 75(5), 368-368. https://doi.org/10.1136/thoraxjnl-2020-214913

Dear Editor, Recent clinical guidelines regarding the use of home non-invasive ventilation (NIV) and continuous positive airway pressure (CPAP) during the COVID-19 epidemic have tried to balance the risks of stopping NIV or CPAP against the unknown p... Read More about Case for continuing community NIV and CPAP during the COVID-19 epidemic.

Comparative Docking to Distinct G Protein–Coupled Receptor Conformations Exclusively Yields Ligands with Agonist Efficacy (2019)
Journal Article
Scharf, M. M., Bünemann, M., Baker, J. G., & Kolb, P. (2019). Comparative Docking to Distinct G Protein–Coupled Receptor Conformations Exclusively Yields Ligands with Agonist Efficacy. Molecular Pharmacology, 96(6), 851-861. https://doi.org/10.1124/mol.119.117515

G protein-coupled receptors exist in a whole spectrum of conformations which are stabilised by the binding of ligands with different efficacy or intracellular effector proteins. Here, we investigate whether three-dimensional structures of receptor co... Read More about Comparative Docking to Distinct G Protein–Coupled Receptor Conformations Exclusively Yields Ligands with Agonist Efficacy.

Pharmacological and SAR analysis of the LINS01 compounds at the human histamine H1, H2 and H3 receptors (2018)
Journal Article
Corrêa, M. F., Barbosa, Á. J. R., Fernandes, G. A. B., Baker, J. G., & dos Santos Fernandes, J. P. (2018). Pharmacological and SAR analysis of the LINS01 compounds at the human histamine H1, H2 and H3 receptors. Chemical Biology and Drug Design, 93(1), 89-95. https://doi.org/10.1111/cbdd.13387

Histamine is a transmitter that activates the four receptors H1R to H4R. The H3R is found in the nervous system as an auto and heteroreceptor, and controls the release of neurotransmitters, making it a potential drug target for neuropsychiatric condi... Read More about Pharmacological and SAR analysis of the LINS01 compounds at the human histamine H1, H2 and H3 receptors.

Novel selective ?1-adrenoceptor antagonists for concomitant cardiovascular and respiratory disease (2017)
Journal Article
Baker, J. G., Gardiner, S. M., Woolard, J., Fromont, C., Jadhav, G. P., Mistry, S. N., …Fischer, P. M. (2017). Novel selective β1-adrenoceptor antagonists for concomitant cardiovascular and respiratory disease. FASEB Journal, 31(7), 3150-3166. https://doi.org/10.1096/fj.201601305R

?-Blockers reduce mortality and improve symptoms in people with heart disease. However, current clinically available ?-blockers have poor selectivity for the cardiac ?1-adrenoceptor (AR) over the lung ?2-AR. Unwanted ?2-blockade risks causing life-th... Read More about Novel selective ?1-adrenoceptor antagonists for concomitant cardiovascular and respiratory disease.

Similarity- and substructure-based development of ?2-adrenergic receptor ligands based on unusual scaffolds (2017)
Journal Article
Schmidt, D., Gunera, J., Baker, J. G., & Kolb, P. (in press). Similarity- and substructure-based development of ?2-adrenergic receptor ligands based on unusual scaffolds. ACS Medicinal Chemistry Letters, https://doi.org/10.1021/acsmedchemlett.6b00363

The ?2-adrenergic receptor (?2AR) is a G protein-coupled receptor (GPCR) and a well-explored target. Here, we report the discovery of 13 ligands, ten of which are novel, of this particular GPCR. They have been identified by similarity- and substructu... Read More about Similarity- and substructure-based development of ?2-adrenergic receptor ligands based on unusual scaffolds.

Pharmacological analysis and structure determination of 7-methylcyanopindolol–bound b1-adrenergic receptor (2015)
Journal Article
Sato, T., Baker, J. G., Warne, T., Brown, G. A., Leslie, A., Congreve, M., & Tate, C. G. (2015). Pharmacological analysis and structure determination of 7-methylcyanopindolol–bound b1-adrenergic receptor. Molecular Pharmacology, 88(6), https://doi.org/10.1124/mol.115.101030

Comparisons between structures of the b1-adrenergic receptor (AR) bound to either agonists, partial agonists, or weak partial agonists led to the proposal that rotamer changes of Ser5.46, coupled to a contraction of the binding pocket, are sufficient... Read More about Pharmacological analysis and structure determination of 7-methylcyanopindolol–bound b1-adrenergic receptor.

Negative cooperativity across ?1-adrenoceptor homodimers provides insights into the nature of the secondary low-affinity CGP 12177 ?1-adrenoceptor binding conformation (2015)
Journal Article
Gherbi, K., May, L. T., Baker, J. G., Briddon, S. J., & Hill, S. J. (2015). Negative cooperativity across ?1-adrenoceptor homodimers provides insights into the nature of the secondary low-affinity CGP 12177 ?1-adrenoceptor binding conformation. FASEB Journal, 29(7), 2859-2871. https://doi.org/10.1096/fj.14-265199

At the β1-adrenoceptor, CGP 12177 potently antagonizes agonist responses at the primary high-affinity catecholamine conformation while also exerting agonist effects of its own through a secondary low-affinity conformation. A recent mutagenesis study... Read More about Negative cooperativity across ?1-adrenoceptor homodimers provides insights into the nature of the secondary low-affinity CGP 12177 ?1-adrenoceptor binding conformation.

Salmeterol's extreme b2 selectivity is due to residues in both extracellular loops and transmembrane domains (2015)
Journal Article
Baker, J. G., Proudman, R. G., & Hill, S. J. (2015). Salmeterol's extreme b2 selectivity is due to residues in both extracellular loops and transmembrane domains. Molecular Pharmacology, 87(1), https://doi.org/10.1124/mol.114.095364

Salmeterol is a long-acting b2-agonist, widely used as an inhaled treatment of asthma and chronic obstructive pulmonary disease. It has very high b2-affinity (log KD 28.95) and is very selective for the b2-adrenoceptor (1000-fold selectivity over the... Read More about Salmeterol's extreme b2 selectivity is due to residues in both extracellular loops and transmembrane domains.

Identification of key residues in transmembrane 4 responsible for the secondary, low-affinity conformation of the human 1-adrenoceptor (2014)
Journal Article
Baker, J. G., Proudman, R. G., & Hill, S. J. (2014). Identification of key residues in transmembrane 4 responsible for the secondary, low-affinity conformation of the human 1-adrenoceptor. Molecular Pharmacology, 85(5), https://doi.org/10.1124/mol.114.091587

The ?1-adrenoceptor exists in two agonist conformations/states: 1) a high-affinity state where responses to catecholamines and other agonists (e.g., cimaterol) are potently inhibited by ?1-adrenoceptor antagonists, and 2) a low-affinity secondary con... Read More about Identification of key residues in transmembrane 4 responsible for the secondary, low-affinity conformation of the human 1-adrenoceptor.