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 alpha(1A)- and beta1-adrenoceptors. It was observed that both --+NH3 group and chiral --OH group of (-)-epinephrine interact with Asp106 TM III of alpha 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 beta1-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 alpha1A- and beta1 adrenoceptors.
(c) 2008 Wiley-Liss, Inc.