Analysis of efficacy of chiral adrenergic agonists

The origin of terms, affinity, intrinsic activity (or efficacy) and spare receptors has been reviewed. The Easson–Stedman theory (1933) in relation to the activation of adrenoceptors by agonists proved to be useful in the analysis of affinity and efficacy. Eudismic ratios of agonists provided critical information about the receptor‐mediated activation. The evidence from circular dichroism spectroscopy with a fluorescent‐tagged adrenoceptor agonist indicates a stereoselective interaction with the receptor. Thus, the simplest definition of efficacy may include the rate of change of the specific conformation of the receptor by the agonist, leading to the organized response. The functional groups of the potent enantiomer are postulated to interact in a “preferred” sequence with the receptor. The 7TM GPCR protein crystal structure of bovine rhodopsin was used as a model to construct the agonist interacting amino acid residues for α 1A ‐ and β 1 ‐adrenoceptors. It was observed that both + NH 3 group and chiral OH group of (−)‐epinephrine interact with Asp 106 TM III of α 1A ‐adrenoceptor. Similar interactions were observed for (+)‐epinephrine but critical differences were observed. Enantiomers of epinephrine and oxymetazoline were also docked in the position at β 1 ‐adrenoceptor to elucidate the conformational changes. Some unique information has emerged about the activation of adrenoceptors by agonists. The differences in the pharmacological efficacy of the enantiomers compare favorably with the dynamics of conformational changes by the agonist at α 1A ‐ and β 1 adrenoceptors. Chirality, 2008. © 2008 Wiley‐Liss, Inc.