Inverse agonism is a pharmacological phenomenon in which a ligand binds to a receptor and activates it, but produces an opposite effect to that of an agonist. Inverse agonists have been studied in relation to G-protein coupled receptors (GPCRs), a class of proteins in the cell membrane that act as signaling molecules. This article will discuss the mechanism and implications of inverse agonism and its role in drug design and development.
GPCRs are integral membrane proteins with seven transmembrane domains that facilitate communication between the extracellular and intracellular environments. Ligands, such as hormones, neurotransmitters, and drugs, bind to GPCRs and activate them to initiate a signaling cascade. Agonists are ligands that activate GPCRs to produce a response, while antagonists bind to the receptor but do not activate it. Inverse agonists are a special class of ligands that bind to the receptor and activate it, but instead of producing an agonistic response, they induce a response opposite to that of an agonist. This phenomenon has been observed in several GPCR classes, including but not limited to serotonin, dopamine, and β-adrenergic receptors (Hewson and Lummis, 2020).
Inverse agonists act on GPCRs by binding to the receptor and causing a conformational change that increases the activity of the receptor. This conformational change results in the activation of a G-protein, which leads to the production of an opposing response to that of an agonist. This opposing response has been observed to lead to reduced receptor activity and decreased downstream signaling (Hewson and Lummis, 2020).
Inverse agonism has implications for drug design and development. Inverse agonists provide an opportunity to modulate the activity of a receptor by targeting the receptor at different levels. For example, some inverse agonists may be able to reduce the activity of the receptor to below baseline levels. This could be beneficial in the treatment of diseases caused by excessive receptor activity, such as hypertension and diabetes (Borroto-Escuela et al., 2020). Additionally, inverse agonists could be used to increase the efficacy of agonists. Combination therapy with agonists and inverse agonists could result in more effective treatments for various diseases.
In conclusion, inverse agonism is a pharmacological phenomenon in which a ligand binds to a receptor and activates it, but produces an opposite effect to that of an agonist. Inverse agonism has been observed in several GPCR classes and has implications for drug design and development, as it provides an opportunity to modulate receptor activity at different levels. Further research is needed to explore the potential of inverse agonists to improve therapeutic outcomes.
References
Borroto-Escuela, D. O., Garrido-Gil, P., Fuxe, K., Ciruela, F., & Agnati, L. F. (2020). GPCR inverse agonism: A new age of opportunities for drug development. Pharmacological Reviews, 72(1), 3-23.
Hewson, A., & Lummis, S. C. R. (2020). G-protein coupled receptor inverse agonism: Mechanism, implications, and therapeutic opportunities. Trends in Pharmacological Sciences, 41(2), 108–124.