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

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

Authors

Jacopo Tricomi

Luca Landini

Valentina Nieddu

Ugo Cavallaro

JILLIAN BAKER jillian.baker@nottingham.ac.uk
Professor of Drug Discovery and Respiratory Medicine

Athanasios Papakyriakou

Barbara Richichi



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 propranolol. 2 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. (in press). Rational design, synthesis and pharmacological evaluation of a cohort of beta-adrenergic receptors ligands enables assessment of structure-activity relationships. European Journal of Medicinal Chemistry,

Journal Article Type Article
Acceptance Date Nov 22, 2022
Deposit Date Nov 24, 2022
Journal European Journal of Medicinal Chemistry
Print ISSN 0223-5234
Publisher Elsevier
Peer Reviewed Peer Reviewed
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