A comprehensive pharmacological analysis of fenoterol and its derivatives to unravel the role of β-adrenergic receptor in zebrafish.

β-adrenergic receptors (βARs) belong to a key molecular targets that regulate the most important processes occurring in the human organism. Although over the last decades a zebrafish model has been developed as a model complementary to rodents in biomedical research, the role of βAR in regulation of pathological and toxicological effects remains to elucidate. Therefore, the study aimed to clarify the role of βAR with a particular emphasis on the distinct role of subtypes A and B of zebrafish βAR. As model compounds selective βAR agonists - (R,R)-fenoterol ((R,R)-Fen) and its new derivatives: (R,R)-4'-methoxyfenoterol ((R,R)-MFen) and (R,R)-4'-methoxy-1-naphtylfenoterol ((R,R)-MNFen) - were tested. We described dose-dependent changes observed after fenoterols exposure in terms of general toxicity, cardiotoxicity and neurobehavioural responses. Subsequently, to better characterise the role of β-adrenergic stimulation in zebrafish, we have performed a series of molecular docking simulations. Our results indicate that (R,R)-Fen displays the highest affinity for subtype A of zebrafish βAR and βAR might be involved in pigment depletion. (R,R)-MFen shows the lowest affinity for zebrafish βARs out of the tested fenoterols and this might be associated with its cardiotoxic and anxiogenic effects. (R,R)-MNFen displays the highest affinity for subtype B of zebrafish βAR and modulation of this receptor might be associated with the development of malformations, increases locomotor activity and induces a negative chronotropic effect. Taken together, the presented data offer insights into the functional responses of the zebrafish βARs confirming their intraspecies conservation, and support the translation of the zebrafish model in pharmacological and toxicological research.