Effects of BRL-47672 on growth, beta 2-adrenoceptors, and adenylyl cyclase activation in female rats

Abstract

The morpholine compound BRL-47672 has a chemical structure similar to that of clenbuterol and causes similar anabolic effects in rats but has no actions on beta 2-adrenoceptors in vitro. It has been argued therefore that beta 2-adrenoceptors do not mediate the anabolic effects of this family of compounds. In the present study BRL-47672 was shown to bind to rat beta 2-adrenoceptors with low affinity (dissociation constant 16 microM) relative to clenbuterol (48 nM) and to be a very weak activator of adenylyl cyclase activity in rat skeletal muscle membranes in vitro. In contrast, acute administration of the drug to anesthetized rats in vivo caused an increase in muscle adenosine 3',5'-cyclic monophosphate output, and chronic treatment of conscious rats for > 6 days caused a significant increase in weight gain (69%) accounted for by increased muscle growth. The anabolic effects of BRL-47672 were not counteracted by daily injections of the drug ICI-118551 (2 mg/day) but were prevented when the same beta 2-antagonist was administered in the diet (200 mg/kg feed, equivalent to 4.3 mg/day). The beta 1-adrenoceptor selective antagonist CGP-20712A fed in the diet (200 mg/kg feed) failed to attenuate the response to BRL-47672. These results support the conclusion that BRL-47672 has little direct action on beta 2-adrenoceptors but suggest that the compound is metabolized rapidly in vivo to a potent beta 2-agonist. Thus the stimulation of muscle growth by BRL-47672 is via beta 2-adrenoceptors, with no contribution to this response from beta 1- or beta 3-adrenoceptor activation.