The intrinsic relative activity of an agonist and its correlation to affinity and efficacy

We investigated a method for estimating the receptor‐dependent component of agonist activity called intrinsic relative activity ( RA i ). This parameter is calculated from the agonist concentration‐response curve, and it represents the product of observed affinity and intrinsic efficacy of an agonist expressed relative to that of a standard agonist. Consequently, RA i should be dependent mainly on the agonist‐receptor‐G protein interaction and unaffected by downstream signaling elements. To validate the RA i analysis, we estimated the affinities and relative efficacies of a series of agonists using Furchgott's method of partial receptor inactivation, and compared the respective product of these two parameters with the corresponding RA i estimate for each agonist. In these experiments, we explored agonist–mediated inhibition of forskolin‐stimulated cyclic AMP production in Chinese hamster ovary cells stably expressing the human M 2 muscarinic receptor. The log product of affinity and efficacy for the agonists, oxotremorine‐M, oxotremorine and S‐aceclidine, expressed relative to carbachol, were 0.782 ± 0.06, 0.641 ± 0.08 and ‐0.369 ± 0.05, respectively. The corresponding log RA i values were 0.653 ± 0.05, 0.748 ± 0.17 and ‐0.183 ± 0.07, respectively. Our results indicate that RA i is a relative measure of the product of affinity and efficacy of an agonist‐receptor complex. Supported by NIH grant 69829 .