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What an Agonist, Partial Agonist, Antagonist, and Inverse Agonist Are

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The largest family of cell surface receptors involved in signal transduction, G protein coupled receptors (GPCRs), are one of the major targets for current drugs as well as new drug development. Ligands interacting with for e.g. adrenergic, histamine, adenosine, opioid, dopamine or serotonin receptors, constitute a large portion of currently used therapeutics

A common property of GPCRs is that upon activation (agonist binding) they transmit signals across the plasma membrane via an interaction with heterotrimeric G proteins.

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Constitutive receptor activity/inverse agonism and functional selectivity/biased agonism are 2 concepts in contemporary pharmacology that have major implications for the use of drugs in medicine and research as well as for the processes of new drug development. Traditional receptor theory postulated that receptors in a population are quiescent unless activated by a ligand. Within this framework ligands could act as agonists with various degrees of intrinsic efficacy, or as antagonists with zero intrinsic efficacy. We now know that receptors can be active without an activating ligand and thus display “constitutive” activity. As a result, a new class of ligand was discovered that can reduce the constitutive activity of a receptor. These ligands produce the opposite effect of an agonist and are called inverse agonists. The second topic discussed is functional selectivity, also commonly referred to as biased agonism. Traditional receptor theory also posited that intrinsic efficacy is a single drug property independent of the system in which the drug acts. However, we now know that a drug, acting at a single receptor subtype, can have multiple intrinsic efficacies that differ depending on which of the multiple responses coupled to a receptor is measured

Thus, a drug can be simultaneously an agonist, an antagonist, and an inverse agonist acting at the same receptor. This means that drugs have an additional level of selectivity (signaling selectivity or “functional selectivity”) beyond the traditional receptor selectivity. Both inverse agonism and functional selectivity need to be considered when drugs are used as medicines or as research tools. It is difficult to overestimate the importance of pharmacology for medicine and research. In medicine, drugs are essential components of a physician’s toolbox to treat disease. In fact, drugs have been used as medicines to treat disease since the beginning of recorded history.

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This maximal efficacy thing is related to several possible mechanisms. Perhaps the partial agonist occupies all the receptors (i.e. achieved full receptor occupancy), and interacts with them in a manner identical to the full agonist, but for some of the receptors it inexplicably fails to activate the ligand binding site or secondary messenger system. The obvious extension of this is where the drug, while binding avidly to the receptors, somehow fails to activate any of them - in which case it is said to be an antagonist

Alternatively, a drug may be a partial agonist because it produces a different distinct structural change in the receptor - for example, an ion channel might open incompletely with a partial agonist, with ionic conductance reduced thereby. The latter effect is observed in the effect of different partial agonists on the acetylcholine receptor (Mukhtasimova & Sine, 2018). Obviously, if a partial agonist drug is used at the same time as a full agonist, and they both act on the same receptors, then the partial agonist will act as an antagonist, competing with the full agonist for a finite number of binding sites. Of the binding sites occupied by the partial agonist, some will not be activated, which reduces the total drug effect. A maximal system response can still be achieved, however - unless the partial agonist binds to the receptor in some sort of irreversible manner, it can be displaced from the receptor by a sufficiently high concentration of full agonist. Thus, the efficacy of the full agonist is not affected, but its potency is reduced.The International Union of Pharmacology Committee on Receptor Nomenclature and Drug Classification (Neubig et al, 2003) give an "official" definition as "Agonist: A ligand that binds to a receptor and alters the receptor state resulting in a biological response".

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In conclusion, there is many ways in which drugs can act on receptors to modify their effect and this can be utilised for treating disease when a system goes out of balance

As mentioned previously, huge advancements have been made since more is now known regarding the structure of receptors and their binding sites. In the future, with more knowledge acquired in this field, further drugs can be manufactured which can be much more specific to their respective receptor and so can produce specific desired effects. This is of particular importance in conditions affecting the brain as disorders such as depression, schizophrenia and Parkinson’s disease are associated with an imbalance in neurotransmitters and improvements in the drugs available to us to treat such conditions will benefit millions of people all around the world.

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Mukhtasimova, Nuriya, and Steven M. Sine. "Full and partial agonists evoke distinct structural changes in opening the muscle acetylcholine receptor channel." The Journal of general physiology 150.5 (2018): 713-729.

Chidiac, Peter, et al. "Inverse agonist activity of beta-adrenergic antagonists." Molecular pharmacology 45.3 (1994): 490-499.

Kenakin, Terry. "Agonists, partial agonists, antagonists, inverse agonists and agonist/antagonists?." Trends in Pharmacological Sciences 8.11 (1987): 423-426.

Pleuvry, Barbara J. "Receptors, agonists and antagonists." Anaesthesia & Intensive Care Medicine 5.10 (2004): 350-352.

Lees, P., F. M. Cunningham, and J. Elliott. "Principles of pharmacodynamics and their applications in veterinary pharmacology." Journal of veterinary pharmacology and therapeutics 27.6 (2004): 397-414.

Ariens, E. J. "Intrinsic activity: partial agonists and partial antagonists." Journal of cardiovascular pharmacology 5 (1983): S8-15.

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