In Defense of Intrinsic Efficacy: The Didactic Value of a Modern Implementation of Furchgott’s Views on Agonism

Abstract

Mastery of fundamental pharmacology concepts is a defining characteristic of basic science graduate pharmacology programs. The acquisition of these skills, however, is challenging for most trainees and a solid understanding of the meaning and use of appropriate pharmacology terms such as efficacy, potency, receptor reserve, allostery and biased agonism is often not fully realized.In an effort to overcome these challenges, I have developed a consistent stepwise approach to the introduction of concepts that involves a modern and expanded implementation of Furchgott’s classical views of agonism. Although largely superseded by the Black and Leff operational model of agonism, Furchgott’s approach has distinct didactic advantages by clearly separating properties of the drug/receptor complex (intrinsic efficacy) from the specific properties of the system that interprets the stimulus generated by the receptor species (sensitivity). This approach lends itself readily to useful didactic analogies that can be implemented and illustrated in the teaching environment and are easier to conceptualize by the learners. To illustrate the behavior of this model, an easy to use simulation tool has been developed in the widely used Excel platform that allows learners to manipulate individual parameters such as affinity, intrinsic efficacy, number of receptors and sensitivity of the system to explore their influence on the shape and position of concentration response and ligand occupancy curves. Furthermore, this formalism is readily expanded in a stepwise manner to introduce progressively more advanced concepts such as interactions between two different ligands, as well as concepts of constitutive activity and allostery. These functionalities are revealed progressively in the simulation tool such that nearly all forms of major scenarios can be explored, including concepts such as receptor reserve, competitive antagonism, inverse agonism, and allosteric effects on both affinity and/or efficacy.The power of this approach is also evidenced by the fact that it is easy to illustrate to the learners not only how different mechanisms can yield similar functional outcomes but also to allow them to explore and identify experiments that can most clearly distinguish between them. This overall didactic approach has proven effective in diverse environments ranging from Medical Student instruction, Doctoral and Masters Pharmacology programs, Doctor in Pharmacy as well as advanced undergraduate courses.Pharmacodynamics simulation tool depicting the functional interaction between an orthosteric and allosteric ligand on two linked responses.Figure 1