Pharmacology's characters: agonists, antagonists and inverse agonists.
- pietrococchiara
- 8 hours ago
- 5 min read
Pharmacology is the branch of the biological sciences which studies the uses, effects, and modes of action of drugs and/or active substances. Several and different types of molecules can behave as active substances towards their cognate receptors (a protein which has the function of induce a biological response upon the specific binding of a molecule called "ligand"). The variety of these substances depends on where they are produced (i.e. secreted) or where they act and which effects they induce in the human body. To better understand how this system functions in general terms, we need to introduce a few basic concepts of pharmacology: agonists, antagonists and inverse agonists.
Definitions: agonists, antagonists and inverse agonists.
Before introducing concepts such as agonist, antagonist and inverse agonist, a premise is required for a better understanding of how these molecules work, known as "receptor theory". Not always a receptor is found on its active state, but it can exist in different conformational states: this means that some receptors can be active and others inactive. Because of the dynamic nature of receptors and proteins in general, this equilibrium between states can be affected by various factors, such as the cell environment, genetic mutations, or the presence of certain molecules acting as agonists, antagonists, or inverse agonists.
An agonist is defined as a chemical substance that can bind to and induce the activation of of specific receptors on cells. These events lead to a certain biological response, whose nature depends on the type of agonist and the type of receptor that has been activated. Therefore an agonist is a molecule with both affinity (it binds to the target receptor) and intrinsic efficacy (it can change receptor activity to produce a response) towards its cognate receptor. The increase of the receptor activity is the results of the stabilization of the receptors itself in its active conformation mediated by the agonist binding.
Instead, an antagonist is defined as a substance that is capable of blocking or inhibiting the action of another substance such as an agonist. This blockade results from the binding of the receptor mediated by the antagonist itself, which does not activate the receptor (differently from an agonist). Therefore, substances acting as antagonists possess affinity towards the receptor, but zero intrinsic efficacy. Their role is mostly related to the occupancy of a fraction of the receptor, reducing, as a consequence, the probability of the agonist to bind the receptor.
Another category of molecules is represented by a group defined as inverse agonists. These are substances that bind to the same receptors as agonists, with the difference that they induce pharmacological responses with opposite effects to those generated by the agonists. This effect is achieved because inverse agonists, when they bind to the receptor, they stabilize it in its inactive conformation, decreasing the receptor activity below the basal level, counteracting the effects of the agonists. Therefore, inverse agonists show affinity, because they bind the target receptor, and negative intrinsic efficacy (because they inhibit the activation of the receptor).
The figure 1 shows graphically what it has been described until now about agonists, antagonists and inverse agonists.
Antagonists and inverse agonists: who is the real "bad guy" of the story?
As previously said, antagonists and inverse agonists exert such a similar effect that is easy to make a mistake when classifying ligands according to their effects towards their cognate receptors. To simplify this story, we could say that the real "bad guy" of the story is the inverse agonist, since it blocks the receptor in its inactive state, "forbidding" it from being activated and exert its biological effect. However, the antagonist, though it binds the receptor, also can prevent its activation, so it may be consider a "facilitator" for the inactivation of the receptor.
These concepts are important to better understand pharmacology. Indeed, some small molecules can act as agonist, antagonist or inverse agonist depending on the specific receptor and the physiological function for which these molecules are produced in our body.
In the next paragraph, an example of this situation will be shown to better clarify this concept.
A chemokines' story: the interchangeability of a chemokine
Chemokines are ligands that bind chemokine receptors and, through them, they regulate several physiological functions in the body, such as the regulation and functioning of the immune system and the embryo's development. Some of these chemokine can bind several types of chemokine receptors, inducing different (and sometimes opposite) effects depending on the specific interaction established.
For example, CCL4, also known as Macrophage Inflammatory Protein-1β (MIP-1β), is a ligand for chemokine receptors CCR1 and CCR5, for which it acts, respectively, as an antagonist and as an agonist. CCL4 can induce chemotaxis, therefore it directs the movement of macrophages and lymphocytes to the site of inflammation or to the region of the infection in the body. While these effects are mostly regulated by CCL4 through binding and activating CCR5, CCL4 has also inhibitory effects towards CCR1. This inhibition has been proven to block the G protein signalling, Ca2+ flux and chemotaxis in cells expressing CCR1, and these signalling pathways are important for the activity of CCR1 in the immune system functioning.
Take-home message
In this article we explored important concepts in pharmacology, which represent basic principle that can be used in drug discovery for developing new therapeutic tools to treat several diseases, but also in medicine, to evaluate the best therapeutic approach to improve patients' health. But these concepts are also useful for everyone who wants to know more about why specific drugs are prescribed to us to treat our physio-pathological conditions! Said that, it is extremely important for scientists to better and clearly identify the role of small molecules towards their target receptors, so new medicines can be developed with a fine rational approach.
References
Bridges, T. M., & Lindsley, C. W. (2008). G-protein-coupled receptors: from classical modes of modulation to allosteric mechanisms. ACS chemical biology, 3(9), 530–541. https://doi.org/10.1021/cb800116f
Negus S. S. (2006). Some implications of receptor theory for in vivo assessment of agonists, antagonists and inverse agonists. Biochemical pharmacology, 71(12), 1663–1670. https://doi.org/10.1016/j.bcp.2005.12.038
Khilnani, G., & Khilnani, A. K. (2011). Inverse agonism and its therapeutic significance. Indian journal of pharmacology, 43(5), 492–501. https://doi.org/10.4103/0253-7613.84947
Chou, C. C., Fine, J. S., Pugliese-Sivo, C., Gonsiorek, W., Davies, L., Deno, G., Petro, M., Schwarz, M., Zavodny, P. J., & Hipkin, R. W. (2002). Pharmacological characterization of the chemokine receptor, hCCR1 in a stable transfectant and differentiated HL-60 cells: antagonism of hCCR1 activation by MIP-1beta. British journal of pharmacology, 137(5), 663–675. https://doi.org/10.1038/sj.bjp.0704907
Ruffing, N., Sullivan, N., Sharmeen, L., Sodroski, J., & Wu, L. (1998). CCR5 has an expanded ligand-binding repertoire and is the primary receptor used by MCP-2 on activated T cells. Cellular immunology, 189(2), 160–168. https://doi.org/10.1006/cimm.1998.1379
Sherry, B., Tekamp-Olson, P., Gallegos, C., Bauer, D., Davatelis, G., Wolpe, S. D., Masiarz, F., Coit, D., & Cerami, A. (1988). Resolution of the two components of macrophage inflammatory protein 1, and cloning and characterization of one of those components, macrophage inflammatory protein 1 beta. The Journal of experimental medicine, 168(6), 2251–2259. https://doi.org/10.1084/jem.168.6.2251
Ren, M., Guo, Q., Guo, L., Lenz, M., Qian, F., Koenen, R. R., Xu, H., Schilling, A. B., Weber, C., Ye, R. D., Dinner, A. R., & Tang, W. J. (2010). Polymerization of MIP-1 chemokine (CCL3 and CCL4) and clearance of MIP-1 by insulin-degrading enzyme. The EMBO journal, 29(23), 3952–3966. https://doi.org/10.1038/emboj.2010.256
Assessed and Endorsed by the MedReport Medical Review Board
