The enantiomers of the hydrophilic beta-adrenergic blocker CGP-12177 have been synthesized and the S-enantiomer radiolabeled with tritium. The dissociation constant (Kd) of the S-enantiomer for binding to the beta-adrenergic receptor is one-half of that of the racemic mixture and at least 2 orders of magnitude lower than that of the R-enantiomer. The kinetic parameters of the latter were determined by analyzing its effect on the association kinetics of (-)-S-[3H]CGP-12177. A computer program was developed that allows the association and dissociation rate constants of unlabeled ligands to be calculated. This method was validated using Monte Carlo simulations. In addition, the rate constants of unlabeled S-CGP-12177 and S-alprenolol calculated using this method were in good agreement with those of S-[3H]CGP-12177 and S-[3H]dihydroalprenolol, respectively, determined independently. The method was also used to measure the rate constants of the enantiomers of pindolol. These antagonists as well as S- and R-CGP-12177 form their receptor complexes with similar association rate constants. In contrast, the dissociation of the R-enantiomers from receptor-ligand complexes were found to be at least 100 times faster than those of the corres...Continue Reading
Adrenergic receptor trafficking is an active physiological process where adrenergic receptors are relocated from one region of the cell to another or from one type of cell to another. Discover the latest research on adrenergic receptor trafficking here.