Efficacy Considerations

Historical receptor theory describes a ligand efficacy continuum, with full agonism at one end and full antagonism at the other. Between the two ends of this continuum lie partial agonists that, as already noted, imply that ligands can also be partial antagonists. Antagonism per se implied that a ligand could bind to a receptor without producing any effect and limiting access to the native agonist-block receptor activation. Such a compound is now called a neutral antagonist.

With the ability to measure constitutive receptor activity, some compounds like the /32-adrenoceptor antagonist, ICI 118551, were found to inhibit constitutive activity, thus functioning as an inverse agonist or negative antagonist (50). The concept of an inverse agonist was first proposed by Braestrup et al. in their studies of the GABAa/BZ receptor complex (51).

Compounds can also have different efficacy properties depending on the system in which they are examined (52) and in an intact tissue preparation can often have distinct agonist and antagonist properties at different receptor subtypes.

Whereas the actions of a competitive antagonism can be surmounted by the addition of increasing concentrations of the agonist ligand, resulting in a functional dose-response curve that undergoes a rightward shirt with approximately the same shape and maximal effect (Fig. 10.1), noncompetitive or uncom-petitive antagonists interact at sites distinct from the agonist recognition site and can modulate agonist binding either by proximal interactions with this site from a site adjacent to the recognition site or by allosteric modulation. The effects of noncompetitive antagonists are usually not reversible by the addition of excess agonist. This type of antagonism, whether competitive or noncompetitive, occurring at a distinct molecular target is known as pharmacological antagonism and involves the interactions between ligands and the receptor site (Fig. 10.4). In contrast, functional antagonism refers to a situation in which an antagonist that does not interact with a given receptor can still block the actions of an agonist of that receptor and is typically measured in intact tissue preparations of whole animal models.

In the hypothetical example shown in Fig. 10.4, neurotransmitter A released from neuron A interacts with A-type receptors on neuron B. Antagonist a can block the effects of A on cell B by interacting with A receptors. Antagonist a is thus a pharmacological antagonist of A receptors. In the second example in Fig. 10.4, neuron A releases neurotransmitter A, which interacts with A-type receptors located on neuron X. In turn, neuron X releases neurotransmitter X that interacts with X-type receptors on neuron Y. Antagonist J3 is a competitive antagonist that interacts with Xre-ceptors to block the effect of neurotransmitter X, and in doing so, indirectly blocks the actions of neurotransmitter A. Antagonist ยก3 is thus a pharmacological antagonist of receptors for the neurotransmitter X, but a functional antagonist for neurotransmitter A. In interpreting functional data in complex systems, it is always important to consider the possibility that a ligand has more than one effect mediated through a single class of receptor. For this reason, in advancing new ligands from in evaluation to more complex tissue systems or animal models, it is extremely helpful to have a ligand-binding profile, e.g., the activity of a compound at a battery of 70 or more receptors and enzymes (a Cerep profile), to fully understand any new findings. For instance, when a ligand for a new receptor is advanced to animal models and found to elicit changes in blood pressure, it would be extremely helpful to know whether in addition to its activity at the new receptor, it has some other properties that relate to the blood pressure effects rather than assuming that some unknown mechanism related to activation of the new receptor has cardiovascular-related liabilities.

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