TABLE 6

Terms and procedures used in the analysis of drug action: agonists

Term Suggested Usage Notes
Desensitization, fade, tachyphylaxis Overlapping terms that refer to a spontaneous decline in the response to a continuous application of agonist, or to repeated applications or doses. The following usages are suggested: fade, the waning of a response in the continued presence of agonist; tachyphylaxis, a decline in the response to repeated applications or doses of agonist. No mechanism is implied by either term. It is recommended that desensitization be used when the fade or tachyphylaxis is considered to be a direct consequence of receptor activation.
Efficacy, e The concept and numerical term introduced by Stephenson (1956) to express the degree to which different agonists produce varying responses, even when occupying the same proportion of receptors. (See also Maximal agonist effect, Table 3). In Stephenson's formulation (1956), combination of an agonist with its receptors is considered to result in a signal or “stimulus” S, which is equated to the product of the efficacy of the agonist A and the proportion of receptors occupied: SA = eApAR
When the response of a tissue is half-maximal, S is assigned the value unity. Hence, a partial agonist that when occupying all the receptors produces a maximal response that is half that of a full agonist (under the same experimental conditions), has an efficacy of unity. Efficacy is both agonist- and tissue-dependent.
The expression intrinsic efficacy, ϵ, was introduced by Furchgott (1966) to denote the notional efficacy associated with a single receptor: e = ϵ[R]T in which [R]T indicates the total concentration of receptors. This term is now also used in a wider sense (see below). Black and Leff (1983) provided another description of differences in the ability of agonists to produce a maximal effect. They defined the term τ (tau) as [R]T/KE in which KE is the midpoint parameter of an explicit function relating receptor occupancy to the response of a tissue. Recent advances in the understanding of receptor function have identified the importance of distinguishing between the occupation of a receptor by an agonist and the activation of that receptor. This distinction was not considered in the earlier work. More detailed models of receptor action are therefore required, and these provide a better framework for expressing, and explaining, differences in the ability of agonists to activate receptors. The term intrinsic efficacy is now often used when discussing the agonist, rather than the tissue-dependent component of efficacy in such schemes [e.g., the isomerization model of del Castillo and Katz (1957), also Colquhoun (1987); the ternary model of DeLean et al. (1980), also Samama et al. (1993)]. However, Stephenson's efficacy, and Black and Leff's τ, can still serve as useful comparative measures of the activity of agonists on intact tissues.
Full agonist When the receptor stimulus induced by an agonist reaches the maximal response capability of the system (tissue), then it will produce the system maximal response and be a full agonist in that system. If the maximum tissue response is reached at less than full receptor occupancy it results in a so-called a spare receptor situation (see below). Several agonists may thus elicit the same maximal response, albeit at different receptor occupancies. They are all full agonists in that experimental system but have different efficacies. This designation of full vs. partial agonist is system-dependent, and a full agonist for one tissue or measurement may be a partial agonist in another.
Inverse agonist A ligand that by binding to receptors reduces the fraction of them in an active conformation (see also agonist, Table 1). This can occur if some of the receptors are in the active form (R*), in the absence of a conventional agonist: An inverse agonist may combine either with the same site as a conventional agonist, or with a different site on the receptor macromolecule (see Table 1).
If the ligand L, combines preferentially with inactive receptors, it will reduce the fraction in the active state:
Intrinsic efficacy See Efficacy (above in this table).
Partial agonist An agonist that in a given tissue, under specified conditions, cannot elicit as large an effect (even when applied at high concentration, so that all the receptors should be occupied) as can another agonist acting through the same receptors in the same tissue (see also Full agonist and Efficacy, above in this table, and Maximal agonist effect, Table 3). As noted for Full agonist above, the designation partial agonist is system-dependent and a partial agonist in one experimental system may be a full agonist in another (e.g., one in which there were more receptors expressed).
Recent advances make it clear that the inability of a particular agonist to produce a maximal response can have several explanations. Perhaps the most important is that not enough of the receptors occupied by the agonist convert to an active form, and the term partial agonist is now sometimes applied to this situation alone.
The distinction between such usages can be illustrated by the action of decamethonium at the neuromuscular junction. Decamethonium cannot match the conductance increase caused by acetylcholine. However, this is not because decamethonium is less able to cause the receptors to isomerize to an active form: rather, the smaller maximal response is largely a consequence of the greater tendency of decamethonium to block the ion channel that is intrinsic to the nicotinic receptor. Hence, decamethonium would not be regarded as a partial agonist with respect to receptor conformational equilibria defined above but would be in the broader sense of the term.
Spare receptors A pharmacological system has spare receptors if a full agonist can cause a maximum response when occupying only a fraction of the total receptor population. Thus not all of the receptors in the tissue are required to achieve a maximal response with some high efficacy agonists. This has been amply demonstrated experimentally by Furchgott (1966) and others in that irreversible chemical inactivation of some receptors results in a decrease in agonist potency without a decreased maximal response. At sufficiently high degrees of receptor inactivation, the maximum response even to full agonists is finally reduced. The term spare receptors is widely misunderstood with some readers thinking that the “spare” receptors are nonfunctional. The phrase receptor reserve means essentially the same thing and may help avoid this confusion though it is less frequently used in the literature. Although all receptors may not be needed for a maximal response, all receptors contribute to the measured responses, thus the potency of full agonists (and often the physiological agonists) is enhanced by the presence of the spare receptors
In analyzing pharmacological properties of ligands or interpreting results with receptor mutants in heterologous expression systems, which often have very high levels of receptor expression, it is essential to understand and account for the spare receptor phenomenon. Many compounds that are partial agonists in normal tissues are full agonists in expression systems due to the high receptor number (see for example, Brink et al., 2000).