A comprehensive pharmacological analysis of fenoterol and its derivatives to unravel the role of ß2-adrenergic receptor in zebrafish.

ABSTRACT

ß-adrenergic receptors (ßARs) 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 ß2AR in regulation of pathological and toxicological effects remains to elucidate. Therefore, the study aimed to clarify the role of ß2AR with a particular emphasis on the distinct role of subtypes A and B of zebrafish ß2AR. As model compounds selective ß2AR 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 ß2-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 ß2AR and ß2AAR might be involved in pigment depletion. (R,R)-MFen shows the lowest affinity for zebrafish ß2ARs 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 ß2AR 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 ß2ARs confirming their intraspecies conservation, and support the translation of the zebrafish model in pharmacological and toxicological research.