27th October 2020
Agonist-Antagonist

Full Agonist, Antagonist, Inverse agonist, Receptor Agonist & Antagonist

Agonist and Antagonist play a vital role in medical history in disease treatment and understanding the underlying mechanism of any pathway of the biological complexity. One often comes across such a word as an agonist, antagonist, inverse agonist, etc. We simply consider it as something which is either similar or dissimilar to the ligand, which can either bind the receptor and or inactivate it or modulate it. But no, we need to understand the mechanism of action and difference between agonist, antagonist, and its every sub-type. Let’s begin the brainstorming.

Agonist

It is a type of ligand when binds to a specific receptor, it would provide a biological response by altering the state of the receptor. It can be endogenous (neurotransmitter and different types of hormones) as well as exogenous (drugs) also.

Agonist

Here A is the agonist, R is the receptor, AR means agonist bound receptor. is a receptor inactivated state.

Full Agonist

Full agonists are ligands which have the capability to give a maximal level of response. Agonists with high efficacy can produce the largest response even when it occupies a very small portion of the receptor.

The relation between the magnitude of response and the occupied available fraction is proportional. It means when the agonist’s concentration increases, it occupies more places and produces a more effective response.

Agonist’s concentration and response magnitude generally provide a hyperbolic shaped curve. If it is represented in a graph by plotting the log of agonist’s concentration against response %, it gives a sigmoidal curve.

Example – Isoprterenol is a full agonist of β- adrenoreceptors that mimic the function of adrenaline. Morphine is another full agonist of the mu-opioid receptor where it mimics endorphin’s function in CNS.

Partial Agonist

In pharmacology, partial agonists are generally the ligands that have the capability to bind at the agonist recognition site of a receptor but the response induced by it is lesser than the full agonist’s response when present in maximal effective concentration. Simply it shows partial efficacy in comparison with full agonist.

The maximum effect generated by a partial antagonist is known as its intrinsic activity which is expressed in percentage (%) where full agonist gives 100%.

If a full agonist is present or available, at that condition a partial agonist function as a competitive antagonist. In this case, partial agonist shows a tendency to occupy the full agonist’s biding site competitively. Depending on this type of feature of partial agonist; it can be utilized for clinical purposes such as inhibiting the over-induction of a receptor in presence of an excessive level of endogenous ligands (1), activating a receptor for producing its submaximal response by introducing it.

An important feature of partial agonists is that it shows the dual type of nature i.e agonistic and antagonistic in different situations. The activity whether it will be acted as an antagonist or agonist varied from substance to substance depending on their intrinsic activities. In presence of a full agonist, it acts as an antagonist, competes with full agonist for the same receptor, and help in decreasing the efficiency of a full agonist (2).

In the classical receptor theory given by Clark, it was suggested that the drug’s response is proportional to the occupied fraction of the receptor by the drug itself. But this concept is only true for a limited number of events. The term “Intrinsic Activity” was introduced by Ariens for clarifying the inconsistency where he stated the correlation between the increased effect by a drug and the concentration of drug-receptor complex.

E =α [DR]

Where E=effect, α =intrinsic activity of a drug, DR = concentration of drug-receptor complex.

Full Agonist

Inverse Agonist

Inverse agonist provides the opposite result of which would be generated if an agonist fixes to the same receptor. It has the ability to reduce the available fraction of receptors which can be active specifically binding at the receptor. Thus helps in decreasing the total probable pool of receptors. In absence of any other drugs if an inverse agonist is introduced to a receptor, then it shows the opposite outcome as compared to normally receptor activation.

As the opposite effect of a normal case is exhibited, this is termed as “Negative Efficacy”. Whenever the full agonist’s maximum efficacy is denoted as 100%, there inverse agonist’s efficacy would be never shown greater than 0%. The activity of the inverse agonists is expressed in a negative % value.

The negative efficacy of an inverse agonist can be decreased by using a competitive ‘neutral’ antagonist (3).

In an article, it has said that the term ‘inverse agonist’ is mainly used to describe for a ligand which has a preference to stabilize G-protein coupled receptor in its inactive state (3).

Inverse Agonist

Example – In the case of GABA receptor, Benzodiazepines acts as an agonist, enhances the effect of GABA receptor by allosteric modulation, and yields anxiolysis and antiepileptic response. Norharmane, a β-carboline derivative is also an allosteric modulator like GABA agonist but functions as an inverse agonist. As Norharmane shows a negative effect on GABA receptors, seizures, angiogenesis are found. In this condition, Flumazenil can be applied as a ‘neutral’ antagonist, reverses the sedating effect of Benzodiazepine and proconvulsant effect of Norharmane.

Antagonist

Antagonists are the substances that prevent the function of an agonist. It can be categorized as competitive and non-competitive. Each of them can do their function either reversibly or irreversibly. If an antagonist binds covalently, then it cannot be easily removed or washed out, thus it shows irreversible binding. In the case of non-covalent binding, it can be easily washed out or can be replaced by other ligands. So the non-covalent binding of antagonist is reversible.

An irreversible type of antagonist is insurmountable and it is not necessary to be non-competitive.

Antagonist

Here N is the antagonist, NR is antagonist bound receptor, is a receptor in an inactive state.

Competitive Antagonist

A competitive antagonist does not activate the receptor although it binds to the exact same site where the agonist binds. Thus prevent the agonist’s activity. Enhancing the concentration of agonists can succeed in the activity of competitive antagonists. In this condition, the agonist’s potency will be decreased but maximum efficacy will not be changed.

Competitive Antagonist Example – Atropine is an example of a competitive antagonist of acetylcholine and other muscarinic agonist’s actions. It goes through the competition for the exact binding site in all muscarinic receptors. In ganglia, intramuscular neuron, exocrine gland, cardiac muscle muscarinic receptor can be blocked by Atropine. Atropine is utilized in Asthma, heart block, cardiac dysrhythmia, etc.

Non-competitive Antagonist

Non-competitive antagonist binds at the non-agonist site in the receptor and blocks the receptor activation and the effect of the agonist. It opposes the action of the agonist without any competition with the agonist for the binding site on the receptor.

There is another term used as a Physiological antagonist. It does not need to have insurmountable property but it is non-competitive (4).

Example of Non-competitive Antagonist–

An example of a non-competitive antagonist is Ketamine at the NMDA glutamate receptor.

At all opioid receptors, Naloxone acts as a competitive antagonist.

Partial Antagonist

The partial antagonist is somehow very similar to the term ‘Partial agonist’. It represents the antagonistic role of the ligand but not with full efficacy. Such as –

The beta-adrenergic blocking agent with sympathomimetic property antagonizes the response of the β-adrenergic receptor when an agonist (noradrenaline/adrenaline) specifically binds in it. But it shows a limited antagonistic response even when β – blockers present on high concentration (5).

Mixed Agonist & Antagonist

It depends on the type of receptor. Where different subtypes of the receptor are present, there one drug can act as an agonist in one subtype of a receptor as well as it can play the role of an antagonist also in another subtype. Simply it means a drug shows dual characteristics in case of different subtypes in the same receptor.

Example –

The opioid receptor has three classical subtypes. These are mu (µ), delta (⸹) and kappa (ĸ). Pentazocine, a drug acts as an agonist at ⸹/ĸ opioid and it can also play an antagonistic role in the µ subtype of opioid receptors.

Buprenorphine plays a partial agonist’s role in the mu receptor but in the kappa-opioid receptors it acts as an antagonist.

Nalbuphine plays an antagonistic role in the mu receptor but shows the agonistic property in the kappa receptor.

Opioid Receptor

Still, now four types of opioid receptors have documented. These are delta(⸹), kappa (ĸ), mu (µ), and ORL-1 (opioid receptor like-1). These are critical for transmission of response and for modulation of different pathways like neurotransmission in the spinal cord, midbrain, limbic system, etc.

Opioid receptors are found ubiquitously throughout the body. Opioid receptors are members of the G-protein coupled receptor (GPCR) family. Within the body opioid system present and interact with several opioid substances. Different receptors are activated by these opioids which transmit the pain response whereas antagonists can block the opioid receptor and influence mood.

It contains seven-transmembrane spanning proteins and is coupled with the inhibitory G protein. After activation, production of adenylyl cyclase is decreased resulting in calcium ion reduction by inhibiting voltage-gated calcium channel followed by K+ channel activation takes palace which leads to hyperpolarization and inhibits neural signal transmission. As a result pain transmission signal is not permitted.

Opioid Partial Agonist

Partial agonist of opioid receptors activates the receptor by binding at specific sites and the response which is given by it is lesser than full agonist on the same receptor.

This type of drug is generally utilized for the development of effective analgesics with less dependence potential and used for treating opiate addiction (6).

Example – Buprenorphine and Tramadol are partial agonists of the mu-opioid receptor.

Buprenorphine is mainly utilized in MAT (Medication Assisted Treatment) to quit the use of different types of opiates like heroin, morphine, etc in the addicted persons. It shows a partial agonistic role in the µ-opioid receptor whereas, in the kappa subtype of the opioid receptor, this same drug exhibits antagonistic behavior.

It shows higher affinity and lesser extrinsic activity at the mu receptor and replaces full agonists like methadone, morphine, etc. Due to the presence of its partial agonist nature, it permeates Buprenorphine certain desirable features such as lower withdrawal discomfort (low physical dependence), more safety in a higher dose than full agonist, lower abuse potential (7).

It occupies a middle point between full agonist (eg-LAAM, Methadone) and antagonist (eg-Naltrexone, Nalmofene).

Opioid Partial Antagonist

Opioid receptors are the specific neurotransmitter receptor works by coupling with G protein activation when stimulated by either endogenous or exogenous compound transduce the signal. Opioid receptor antagonists are a type of ligand having the ability to block the response of one or more opioid receptors.

Example –

Methylnaltrexone is an example of an effective competitive antagonist that acts on the digestive tract and used for opioid-induced constipation (8).

The administration of Naloxone is mostly done in the case of alcohol used disorder to maintain abstinence. It is a competitive antagonist of the mu receptor and increases alertness, stimulates respiratory drive, terminates euphoria, and analgesia and can cause mydriasis (9).

When the performance of the antagonist is not at the maximum level or gives partial response even when occupies the whole opioid receptor, it can be termed as a partial antagonist of the opioid receptor.

Receptor Agonist & Antagonist

Pharmacologically receptor recognizes a specific shape of molecules for binding and exerting a physiological response within the body. Receptors are classified into four different categories –

i. G-protein coupled receptor (GPCR) ii. Ligand-gated ion channels iii. Enzyme-linked receptor and iv. Intracellular receptor.

ii. GPCRs are found only in eukaryotic cells including yeast, animals, choanoflagellates. Neurotransmitters, hormones, pheromones, odors can activate this type of receptor (3). When ligands bind on this receptor it functions as guanine exchange factor (GEF) along with conformational changes. Then it activates the G protein associated with it with the help of GTP.

iii. Ligand-gated ion channels or ionotropic receptors allow Na+, Ca2+, K+, and/or Cl to pass via a membrane.

iv. An enzyme-linked receptor is also termed as the catalytic receptor. It binds with ligands in the extracellular domain which introduces a conformational change in the receptor’s catalytic site and activates the intracellular enzymatic activity.

v. Intracellular receptors are mainly located inside the cell which interacts mainly with ligands having hydrophobic properties so that these will be able to cross the membrane easily.

The agonist occupies the receptor site and helps in its functioning for signal production and the antagonist antagonizes the agonist’s function and does not permeate the receptor to give receptor.

Examples of agonist and antagonist of the GPCR receptor

Agonist – Morphine – for opioid receptor

Antagonist – fexofenadine – for Histamine H1 receptor

Antagonist – haloperidol – for Dopamine receptor

Antagonist – Atropine – for muscarinic receptor

Examples of agonist and antagonist of ionotropic receptor

Agonist – Glutamate, Domoic acid – for AMPA receptor

Antagonist – Kynurenic acid – for AMPA receptor.

Agonist – Quinolinate – for NMDA receptor.

Antagonist – Ketamine, tramadol – for NMDA receptor.

Agonist – GABA, gaboxadol – for GABA receptor.

Antagonist – bicuculine – for GABA receptor.

β – Blocker

β- Blockers are under the category of competitive antagonist that basically blocks the binding site of endogenous catecholamine (i.e epinephrine, nor-epinephrine) on the adrenergic receptor(10). As it interferes in the binding so it weakens the biological response also.

It occurs in the sympathetic nervous system where hyperarousal response (fight or flight response/ acute stress response) is observed (11, 12). β- Adrenergic receptors are different types like β1, β2, and β3 which are present in a different part of the body.

β1 – in kidney and heart muscle mainly (12).

β2 – in the gastrointestinal tract, liver, lungs, uterus, skeletal muscle, smooth muscle, etc (12).

β3 – in adipose tissue (13).

In the heart, β1 activity can influence the Renin-angiotensin system. β-blocker may reduce renin release as an outcome it decreases the oxygen demand of the heart by increasing oxygen-carrying capability and by reducing extracellular volume.

Uses of Beta-Blockers

Beta-blockers are used as medications for treating abnormal rhythm of the heart and for providing protection against myocardial infarction (14). Sometimes they are used for hypertension (15), cardiac arrhythmia (15, 16), angina pectoris (15,17,18), hyperthyroidism (15).

During the time of cardiac surgery, the introduction of beta-blockers reduces the risk of dysrhythmia in the heart (19).

The intrinsic sympathomimetic activity of beta-blockers

Beta-blockers display both agonistic as well as antagonistic behavior at a specific receptor by depending on the concentration of the endogenous compound and the concentration of itself. A group of beta-blockers that have the capability to bind in beta-adrenergic receptors agonistically and on the other side it can inhibit the stimulatory effect of catecholamines antagonistically in a competitive way, these are recognized as a substance which has intrinsic sympathomimetic activity (ISA).

If beta-blocker with ISA is introduced then lesser resting bradycardia and lower decrease in cardiac output are exhibited than without ISA beta-blocker. In the case of long term treatment, ISA showing beta- blocker does not give an adverse response for plasma lipoproteins.

For the ISA property, β-adrenoreceptor up-regulation can be counteracting by beta-blockers which cannot occur without ISA. But there are certain conflicts arises for using these beta-blockers (with ISA) in secondary prevention case after myocardial infarction (10). Several beta-1 related blocking drugs like acebutolol shows ISA, this is also recognized as a partial agonistic activity.

Drugs with ISA property are an effective therapeutic approach especially for coronary artery disease (20). As a drug with ISA may initiate down-regulation of beta receptors; so after the withdrawal of that drug, there would be no post-beta-blocking drug hypersensitivity which can occur in the case of drugs without ISA. According to certain evidence, drugs with ISA give lower disturbance in certain metabolic processes especially in lipid metabolism (21).

Example – This type of beta-blockers are – pindolol, acebutolol, penbutolol, oxprenolol which show intrinsic sympathomimetic activity (ISA). This type of beta-blocker would not be beneficial for treating excessive bradycardia.

In the case of angina and tachyarrhythmia, these are not useful as it has exhibited less effectiveness (22).

References

  1. Zhu BT (April 2005). A mechanistic explanation for the unique pharmacologic properties of receptor partial agonists. Biomedicine & Pharmacotherapy. 59(3):76-89.
  2. Calvey N, Williams N (2009). Partial agonists. Principles & Practice of pharmacology for Anasthesists, p-62.
  3. Pleuvry, Barbara J. Receptor Agonists and Antagonist. Anesthesia and Intensive Care Medicine 5, 10(2004):350-352.
  4. Wyllie DJ, PE Chen. Taking the time to study competitive antagonism.
  5. Ariens E J. Intrinsic Activity: Partial agonists and partial antagonists. Journal of Cardiovascular Pharmacology 5(1983): S8-15.
  6. JJC Jacob, GM Michaud & EC Tremblay. Mixed agonist-antagonist opiates and physical dependence. Br.J.Clin.Pharmac (1979) 291S-296S.
  7. Hasan Patan & John Williams.Basic opioid pharmacology: an update. Br. J. Pain, 2012: 6(1):1-16.
  8. Thomas J, Kanver S, Cooney GA, Chamberlian BH, Watt CK, Slatkin NE, Stambler N, Kremer AB, Israel RJ.Methylnaltrexone for opioid-induced constipation in advanced illness. N.Engl.J.Med.2008 May29;358(22):2332-43.
  9. Waldhoer M,Bartlett SE, Whistler JL. Opioid Receptor.Anu.Rev.Biochem.2004;73:953-90.
  10. P Jaillon. The relevance of intrinsic sympathomimetic activity for beta-blockers. Am J Cardiol. 1990 Sep 25;66(9):21C-23C.doi: 10.1016/0002-9149(90)90758-s.
  11. Frishman WH, Cheng-Lai A, Naworskos J (2005). Current cardiovascular drugs. Current Science group. P- 152.ISBN 978-1-57340-221-7. Retrieved September 7, 2010.
  12. Arcangelo VP, Peterson AM (2006). Pharmacotherapeutics for advanced practice: a practical approach. Lippincott Williams & Wilkins. P- 205.ISBN 978-0-7817-5784-3.Retrieved September 7, 2010.
  13. Clement K, Vaisse C, Manning BS, Basdevant A, Guy Grand B, Ruiz J, Silver KD, Shuldiner AR, Froguel P, Strosberg AD(Aug 1995). Genetic variation in the beta 3-adrenergic receptor and an increased capacity to gain weight in patients with morbid obesity.The New England Journal of Medicine. 373(6):352-4.
  14. Freemantie N, Cleland J, Young P, Mason J, Harrison J.(June 1999).Beta blockage after myocardial infraction: systemic review & meta-regression analysis; BMJ.318(7200):1730-7.
  15. Katzung, Bertram (2018). Basic & Clinical Pharmacology. McGraw-Hill.ISBN 9781259641152.
  16. Medication for Arrhythmia. www.heart.org.Retrieved Aug 10, 2019.
  17. Khan MI, Gabriel (2007). Cardia Drug Therapy.Human Press.ISBN 978-1-59745-238-0.
  18. Cteophan Ton (1995). Beta-blockers in hypertension & angina pectoris: different compounds, different strategies. Kluwer Academic Publishers. ISBN 978-0-7923-3516-0.
  19. Blessberger H, Kammler J, Damanovits H, Schlager O, Wildner B, Azar D, Schillinger M, Wiesbauer F,Steinwender C (March 2018). Perioperative beta blocker for preventing surgery related mortality and morbidity. The Cochrane Database of Systematic Reviews. 9(9): CD004476.
  20. S H Taylor. Role of cardioselectivity and intrinsic sympathomimetic activity in beta-blocking drugs in cardiovascular disease. Am J Cardiol. 1987 May 15;59(13):18F-20F.doi: 10.1016/0002-9149(87)90036-1.
  21. B N Prichard. Pharmacologic aspects of the intrinsic sympathomimetic activity in beta-blocking drugs. Am J Cardiol. 1987 May 15;59(13):13F-17F. DOI: 10.1016/0002-9149(87)90035-x.
  22. Rossi S, ed (2006). Australian Medicine Handbook.

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