Affinity of clenbuterol analogues for beta 2-adrenoceptors in bovine skeletal muscle and the effect of these compounds on urinary nitrogen excretion in female rats

Abstract

The longissimus dorsi muscles of cattle are highly responsive to the anabolic effects of beta 2-adrenoceptor agonists, and in the present study were shown to be a rich and homogeneous source of beta 2-adrenoceptors. Structural analogues of the beta 2-adrenoceptor agonist clenbuterol were prepared in order to examine the relative importance of the benzylic hydroxyl functionality and the aromatic ring halogen substituents in determining the affinity of phenylethanolamines for beta 2-adrenoceptors in bovine muscle. It was calculated that the hydroxyl-hydrogen bonding interaction of these compounds contributes only 1-2 kcal/mol to the total binding energy. The aromatic halo-substituents contributed up to 3 kcal/mol to the total binding energy, and we suggest that the relative importance of the latter functionality has been previously underestimated. There was a poor correlation between the affinity of clenbuterol analogues for binding to beta 2-adrenoceptors, and the potency of these compounds in reducing urinary nitrogen excretion after oral administration to female rats. We suggest that beta 2-adrenoceptor agonist efficacy is reduced in phenylethanolamine compounds when iodine is present on the aromatic ring. In contrast, the increased potency of a ketone derivative might be explained by conversion in vivo to clenbuterol, with increased bioavailability of this beta 2-agonist at the site of action.