Rational design, synthesis, and pharmacological evaluation of a cohort of novel beta-adrenergic receptors ligands enables an assessment of structure-activity relationships

Tricomi, Jacopo; Landini, Luca; Nieddu, Valentina; Cavallaro, Ugo; Baker, Jillian; Papakyriakou, Athanasios; Richichi, Barbara

Abstract

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, including cancer. Despite successes in β-AR drug discovery, identification of β-AR ligands that are useful as selective chemical tools in pharmacological studies of the three β-AR subtypes, or lead compounds for drug development is still a highly challenging task. This is mainly due to the intrinsic plasticity of β-ARs as G protein-coupled receptors in conjunction with the requirement for functional receptor subtype selectivity, tissue specificity and minimal off-target effects. With the aim to provide insight into structure-activity relationships for the three β-AR subtypes, we have synthesized and obtained the pharmacological profile of a series of structurally diverse compounds (named MC) that were designed based on the aryloxy-propanolamine scaffold of SR59230A. Comparative analysis of their predicted binding mode within the active and inactive states of the receptors in combination with their pharmacological profile revealed key structural elements that control their activity as agonists or antagonists, in addition to clues about substituents that mediate selectivity for one receptor subtype over the others. We anticipate that these results will facilitate selective β-AR drug development efforts.

Citation

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

• Journal Article Type: Article
• Acceptance Date: Nov 22, 2022
• Online Publication Date: Nov 29, 2022
• Publication Date: Jan 15, 2023
• Deposit Date: Nov 24, 2022
• Publicly Available Date: Nov 30, 2023
• Journal: European Journal of Medicinal Chemistry
• Print ISSN: 0223-5234
• Electronic ISSN: 1768-3254
• Publisher: Elsevier
• Peer Reviewed: Peer Reviewed
• Volume: 246
• Article Number: 114961
• DOI: https://doi.org/10.1016/j.ejmech.2022.114961
• Keywords: G-protein-coupled receptors; β-adrenergic receptors; aryloxy propanolamine; molecular docking; β-blocker; β-agonist; β-antagonist
• Public URL: https://nottingham-repository.worktribe.com/output/14036453
• Publisher URL: https://www.sciencedirect.com/science/article/pii/S0223523422008637?via%3Dihub