Expressing the Maximal Response to a Partial Agonist Intrinsic Activity and Efficacy

2 Expressing the Maximal Response to a Partial Agonist Intrinsic Activity and Efficacy 

In 1954 the Dutch pharmacologist E. J. Aliens introduced the term intrinsic activity, which is now usually defined as  

An important difference from Ariens s concept of intrinsic activity is that efficacy, unlike intrinsic activity, has no upper limit it is always possible that an agonist with a greater efficacy than any existing compound may be discovered. Also, Stephenson s proposal was not finked to any specific assumption about the relationship between receptor occupancy and the response of the tissue. (Ariens, like A. J. Clark, had initially supposed direct proportionality, an assumption later to be abandoned.) According to Stephenson, 

y is the response of the tissue, and eA is the efficacy of the agonist A. f(SA) means merely some function of SA (i.e., y depends on SA in some as yet unspecified way). Note that, in keeping with the thinking at the time, Stephenson used the Hill-Langmuir equation to relate agonist concentration, [A], to receptor occupancy, pAR. This most important assumption is reconsidered in the next section. 

In order to be able to compare the efficacies of different agonists acting through the same receptors, Stephenson proposed the convention that the stimulus S is unity for a response that is 50% of the maximum attainable with a full agonist. This is the same as postulating that a partial agonist that must occupy all the receptors to produce a half-maximal response has an efficacy of unity. We can see this from Eq. (1.27) if our hypothetical partial agonist has to occupy all the receptors (i.e., p = 1) to produce the half-maximal response, at which point S also is unity (by Stephenson s convention), then e must also be 1. 

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