Letter regarding Pini, A., Nardini, P., Zizi, V., Molino, M., Calvani, M., Carrozzo, F., … Filippi, L. (2026). β ₃ ‐adrenoceptor agonism exerts lung protection in a rat model of bronchopulmonary dysplasia. Br J Pharmacol, in press

We read with great interest the article by Pini and colleagues showing that BRL 37344 exerts a protective effect in a rat model of lung injury, typically found in preterm infants who have undergone mechanical ventilation (Pini et al., 2026). While the biological effects of BRL 37344 are interesting, the authors conclusions that this demonstrates a role for β3-adrenoceptors as a pharmacological target in preterm infants propagates the long debunked myth that BRL 37344 is a selective β3 receptor agonist. It is not. The affinity (pKi) of BRL 37344 as determined in radioligand binding studies is almost identical at cloned human β2 and β3-adrenoceptors (6.51 vs. 6.45) (Baker, 2010). In at least some cAMP formation studies, BRL 37344 was even more potent at human β2 and β3-adrenoceptors (EC50 153 vs. 728 nM) (Kanie et al., 2012). Specifically, agonists need a high degree of subtype selectivity in molecular studies because differences in receptor reserve of subtypes across tissues and cell types may outweigh the possible benefits of moderate selectivity (if it was present) at the receptor level. Perhaps most importantly, several functional in vitro and in vivo effects of BRL 37344 were shown to be sensitive to propranolol, that is, unlikely to be mediated by β3-adrenoceptors. This includes positive inotropic effects in human myocardium or dilatation of retinal arterioles, blood pressure lowering and heart rate increases in rats (for review, see Michel et al., 2010). Of note, effects of the more β3 selective agonist CL316243 in the latter study were insensitive to propranolol, whereas those of BRL 37,344 were not. In other words, BRL 37344 can elicit bona fide β3-adrenoceptor responses but not necessarily via the β3-adrenoceptors but via other β-adrenoceptors subtypes. To complicate the picture further, BRL 37344 has shown an affinity to some subtypes of the α1-adrenoceptors and of the muscarinic receptor comparable to those at β3-adrenoceptors (Michel et al., 2010). Accordingly, the Concise Guide to Pharmacology concludes that BRL 37344, if anything, is moderately selective for β3- over β2-adrenoceptors only in mice (Alexander et al., 2025). In summary, the data presented by Pini and colleagues do not allow the conclusion that the observed effects of BRL 37344 in a rat model of lung injury are specifically mediated via β3-adrenoceptors. This creates considerable uncertainty over the proposal that β3-adrenoceptors may be a target for the treatment of this condition. Before β3-adrenoceptors can be considered as a new therapeutic intervention in critically ill preterm infants, it must be demonstrated that these effects are sensitive to selective β3 agonists, insensitive to propranolol and/or are mimicked by rodent β3 agonists such as CL316243 or human agonists such as mirabegron or vibegron. Torsten Christ: Conceptualization; writing—original draft; writing—review and editing. Martin C. Michel: Conceptualization; writing—original draft; writing—review and editing. MCM has received consultancy and speaker honoraria from Pierre Fabre Laboratoires. TC declare no conflict of interest.