Efficacy
Efficacy refers to the property of an agonist that allows the agonist to activate a target protein following binding to the protein. While an antagonist can bind to a protein and evoke a structural change that does not result in activation of the protein (the induced-fit model) or bind to an inactive conformational state of a protein (the conformational selection model), an agonist can evoke a structural change in the protein that does activate the protein, or can bind to an active conformation of the protein. As such, “efficacy” does not refer to an “activity” associated with an agonist molecule as such, but simply to the ability to elicit a cellular response as a result of structural properties of the agonist molecule that just happen to result in a shift in the protein’s structure that causes activation. For example, if the protein target is a ligand-gated ion channel, binding of an agonist would increase the likelihood of the channel existing in an “open pore” conformation that allows ions to flow, whereas the protein’s response to binding of an antagonist would not result in an open-pore conformation.
The following details provide a more in-depth explanation of the nature of efficacy.
Binding of an agonist to a receptor results in activation of a signal transduction system within the cell, which is usually a multi-step process that amplifies the single binding event of an agonist associating with a single receptor to cause multiple, repeated events, or a magnified response, within the cell. For example, binding of an agonist may open a sodium channel, allowing positively-charged sodium ions to flow into the cell. If enough ions are able to flow through one channel during the target residence time of the agonist (see the manual entry under affinity for further discussion of target residence time), or, more likely, through multiple channels each opened by an agonist molecule, to cause a depolarisation of the cell beyond a threshold level, then opening of voltage-activated calcium channels in the cell membrane will occur. This allows calcium ions to flood into the cell and interact with a large number of calcium-sensitive proteins such as calmodulin, leading to cellular responses including, for example, smooth muscle contraction or stimulation of glycolysis.
With respect to this example, an agonist with high efficacy may be able to open the sodium channel protein for a longer period of time, or to open the channel pore to a larger diameter, compared with effects of an agonist with lower efficacy. Both of these effects would result in more sodium ions flowing into the cell following binding of a single high efficacy agonist to a single receptor, compared with the result of binding of a single low efficacy agonist to a single receptor. As a consequence of this, it may be necessary for the lower efficacy agonist to be present at a higher relative concentration than the high efficacy agonist in order to evoke a response of similar magnitude, because the lower efficacy drug needs to activate more receptors for a longer period of time to facilitate the influx of sufficient sodium necessary to reach the subsequent depolarisation threshold.
From the discussion above, we can draw the conclusion that an agonist does not necessarily need to activate all of the receptors on a cell surface in order to initiate a response from the cell. Indeed, if it was necessary to occupy all of the receptors (b/Bmax = 1), the concentrations of agonist required would be incredibly high (in theory, infinitely high). However, that is not the case. For a cell with 1000 receptors expressed on its surface, an agonist with high efficacy may only need to bind and activate 20 receptors (2%) to evoke a maximum response from the cell, whereas an agonist with lower efficacy may need to bind and activate 200 receptors (20%) to evoke a maximum response. The proportion of receptors that are not required by the agonist (i.e. 98% for the first agonist and 80% for the second agonist) are referred to as spare receptors, or sometimes as the receptor reserve. Efficacy can be given a numerical value to allow more quantitative comparisons to be made between different agonists, and this value is related to the proportion of a population of receptors for a particular agonist in a particular tissue that must be activated in order to evoke a maximum response from that tissue. The details of how to determine this value are complex and are far beyond what a clinician should understand on the topic. However, in general terms, the lower the proportion of the total receptor population that is required by an agonist to evoke a maximum tissue response, the higher the efficacy of that agonist.
The biological impact of spare receptors is to increase the efficiency of endogenous agonists. This is explained further in the manual entry under spare receptors.
Any agonist that is able to evoke a maximum response in a cell is referred to as a full agonist. As such, any agonist that has spare receptors or a receptor reserve in a particular tissue is, by definition, a full agonist in that tissue. However, some agonist drugs are unable to evoke a maximum response in a tissue even when they are present at concentrations high enough to occupy all of the receptors. These drugs are referred to as partial agonists in that particular tissue.
The efficacy of a particular agonist that activates a particular type of receptor varies between different tissues (and thus different cell types) in which that receptor is located. This is because different cell types express different numbers of receptors, while signal transduction systems may also vary in their efficiency in different cell types. As a result, it is possible for a drug to be a full agonist in one tissue and a partial agonist in another tissue, and for this reason, it is not appropriate to state that a drug is a full agonist or a partial agonist without also identifying the tissue or organ in which the receptors are located. What does not vary, though, is the relative efficacies of different agonists; if agonist X has 5-fold higher efficacy than agonist Y in one tissue, it will also have 5-fold higher efficacy in a different tissue, regardless of differences in the actual efficacy values for drug X in the two tissues. This is a critical point with respect to drug discovery, since drugs are often tested in tissue systems expressing the target of interest that are not the tissues in which the drug is ultimately designed to act when administered to a patient. A potential new agonist drug may show low efficacy and elicit a rather weak response in a test system, but if an established agonist known to show high efficacy in a patient shows low efficacy in the test system that is only marginally better than that of the novel drug, then the novel drug will show high efficacy, close to that of the established agonist, in a patient. This is the basis for the Operational Model for Agonism, a procedure for determining agonist efficacy and extrapolating to predict efficacy in different tissues, developed by Scottish pharmacologist and Nobel laureate, Sir James Black.
