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Partial agonists

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Partial agonists are ligands or drug compounds that bind to receptors and trigger a submaximal response that is weaker than that of full agonists. Partial agonists are a sub-type of agonists, and they all possess intermediate intrinsic activity falling between that of full agonists and antagonists.[1][2]Due to their limited efficacy, partial agonists exhibit the ceiling effect, where their maximum response plateaus and does not increase beyond a certain level, distinguishing them from full agonists.[3]

Due to the ceiling effect, partial agonists exhibit a dual nature, allowing them to act like full agonists or antagonists depending on the context.[1] In the absence of full agonists, partial agonists will stimulate receptors to produce an intermediate response; However, when full agonists are present, partial agonists will occupy receptors with less response, effectively acting as competitive antagonist.[1]

Clinically, partial agonists showcase balanced therapeutic effects and improved safety profiles.[4] The balanced activity of partial agonists minimize the excessive receptor stimulation, reducing risk of side effects; At the same time, the minimal level of response is increased.[4][5] There are currently available medications, such as Aripiprazole, Buprenorphine, and Varenicline, that have places in therapy in different conditions. Ongoing researches are being done to evaluated the potential of more partial agonists, such as serotonin 5-HT1A receptor partial agonist.[6]

Mechanism of action

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Agonists, including partial agonists, are ligands or compounds that can produce a physiological response by binding to their target sites, usually a type of receptors in the human body.[4][5] This binding activates the target, often causing a conformational change in the receptor and triggering the subsequent signalling pathway, eventually leading to the response mediated by the receptor.[1][4]The receptors that partial agonists bind to are also receptors that full agonists or endogenous ligands bind to, hence partial agonists will compete with these molecules for receptor binding.[1]

Agonists

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Type Effect Examples Antagonist Interaction
Full agonist Bind to receptor and change its conformation to the fully active state, mimicking endogenous ligands and producing a maximal response.[4][7] Blocked by competitive antagonists and no effect in absence of the agonist.[1][4]
Partial agonist Bind to receptor and partially activate the receptor, increases activity from baseline but not to maximum, even at saturating levels.[2][4] Can act as a weak agonist or antagonist depending on situation.[1]
Inverse agonist Bind to receptor and stabilize its inactive conformation, lowering its spontaneous activity and exerting a negative response.

Reverses the inverse agonist’s effect, returning the receptor to its baseline constitutive activity.[4]

Parameters for partial agonist activities

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When describing the activity of ligands or drugs, there are different parameters that can be used. One of the most important is efficacy, which is capable of defining the unique property of partial agonists and distinguishing them from full agonists.[4][8]

Efficacy

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Efficacy of full agonist, partial agonist, antagonist and inverse agonist

Efficacy, or Intrinsic activity, refers to the capability of ligands to activate a receptor or the highest level of response that it can produce.[1][4][9] In general, partial agonists have a lower intrinsic activity than full agonists, meaning that they can only induce conformational change of the target to a smaller extent.[1][2] On a scale of intrinsic activity, full agonists have an intrinsic activity of 1 (or 100%), as they can produce the maximal response, while the intrinsic activity of full antagonists is 0 (or 0%), as they bind to receptors without producing any effect.[4][10] Partial agonists, on the other hand, always lie somewhere in between.[4][10]

A vast majority of full agonists, due to their high intrinsic activity, do not require 100% receptor occupancy to exert their maximal effect.[1] In such cases, there will be spare receptors - receptors that remain unbound. In contrast, for partial agonists, due to their intermediate ability to induce response, they can never match the maximal responses induced by full agonist despite occupying all available receptors with no spare receptors left.[1][4]

Other parameters

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Different potency shown on dose-response graph. It is not directly correlated with intrinsic activity or efficacy.

Other important parameters include selectivity, affinity, and potency, which describes respectively the specificity, strength, and efficiency of the binding of ligands to receptors.[1][4][11] These parameters are related to the binding activity and are not directly proportional to efficacy, which describes the magnitude of response of ligand binding. Therefore, these parameters can vary greatly depending on specific molecular structures and receptor dynamics.[4] In terms of these parameters, there is no clear difference between full agonists and partial agonists, and hence cannot be used to distinguish full agonists from partial agonists.[12] For instance, It is possible for partial agonists to be more potent than full agonists, and hence produce a relatively stronger response at the same, low concentration.[12]

Therefore, full agonists do not necessarily produce stronger effects than partial agonists – it depends on the ligand property and specific context, such as concentration.

Pharmacodynamic effect

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The effect of partial agonists can be demonstrated by the dose-response curve of partial agonists, in comparison to that of full agonist.[4]

Dose-response curve

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Comparison of dose–response relationship of partial agonist and full agonist

When the concentration of compounds is low, dose-response curve of both partial agonists and full agonists show a similar pattern: the level of response increases with the concentration of the compound, following the classic dose-response relationship.[13] However, for partial agonists, once a certain concentration is reached, the increase in level of response becomes progressively smaller with each increase in concentration.[4]

As concentration increases, the response eventually reaches a plateau, indicates the maximal response of partial agonists which is always below that of full agonists.[5][4] This plateau represents the ceiling effect, a key characteristic of partial agonists.[3] Beyond this point, increasing the dose of a partial agonist fails to produce further response. It is after the ceiling effect occurred that partial agonists can exert their antagonizing effect by competing with full agonists.[3]  

Dual property of partial agonists

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Partial agonists possess both agonistic and antagonistic properties.[1] Depending on the presence of other ligands, such as full agonists, partial agonists can either stimulate or "inhibit" their targets. This dual property is derived from their intermediate intrinsic activity, which is in-between that of full agonists and full antagonists.[1][4]

When full agonists are absent, there will not be any receptor stimulation and responses.[4][14] Under this low activity state, partial agonists will act as weak agonists as they can bind to the receptors to produce submaximal responses.[14] This allow the minimal response level to rise when partial agonist and full agonist are present together.[15]

However, when the concentration of full agonist is high, partial agonists will act like weak competitive antagonists instead.[4][14] Under this high activity state, partial agonists and full agonists will compete with each other for the available receptors[4]. As responses produced by partial agonists are relatively weaker, the overall level of effect produced at last will be lower compared to full agonists alone.[1] This is different from antagonists, which can completely inhibit the response and reduce response to zero if the concentration is high.[4][1]

Therapeutic applications (clinical use)

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Generally, partial agonists is used clinically for obtaining a safety profile with less risk of side effects or preventing the excessive stimulation of receptors.[4]

Currently available medications

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Aripiprazole

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Image of Abilify, generic aripiprazole tablets launched by Teva Pharmaceutical Industries Ltd.[16]

Aripiprazole is a second generation antipsychotic for treatment of schizophrenia, which targets D2 receptors in the mesolimbic dopaminergic pathway.[17] Due to the partial agonist properties of Aripiprazole, the medication serve as both a antagonist and agonist and does not exert maximum response, a certain degree of dopamine receptor stimulation pathway can be conserved when given an effective dose.[18]

As a result, when the drug is given high dose or overdosing happens, in which a high occupancy of dopamine 2 receptors is achieved, Aripiprazole has a generally lower risk of inducing Extrapyramidal symptoms (EPS) than full D2 receptor antagonists such as Olanzapine and Ziprasidone.[18] In addition, partial antagonism also contributes to the higher effectiveness of aripiprazole in managing depressive symptoms.[19]


Beta blockers with intrinsic sympathomimetic activity

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Beta blockers with intrinsic sympathomimetic activity (ISA), such as acebutolol and pindolol, are considered partial agonist.[4] With the ability to stimulate heart slightly, beta blockers with ISA are less likely to cause reduction in cardiac output and resting bradycardia compared to other beta-blockers, and hence they are better tolerated in patients with compromised cardiac function.[4][20]

In long term, beta blockers with ISA can induce arterial vasodilation and increase arterial compliance which is beneficial in hypertension management.[20] In addition, acebutolol may also be effective in lowering the mortality rate of patients after myocardial infraction, which is shown to be associated with partial agonist activity.[20]

Moreover, beta blockers with ISA may be more beneficial for the lipid profiles of patients. Compared to the decrease in HDL level induced by non-selective and beta 1 selective beta blockers, beta blockers with ISA can lead to an elevation of HDL level while inducing the least increase in triglyceride level.[20]

Buprenorphine

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Buprenorphine is one of the first-line choice in the Management of opioid use disorders and is widely used in the context of the opioid epidemic in the United States.[21]

Partial agonist activity of Buprenorphine

Buprenorphine is a weak partial agonist that acts on opioid receptors, serving as a potent analgesic and an opioid abuse deterrence alternative to methadone.[22] Despite being approximately 100 times more potent than morphine, buprenorphine can provides its pain relief effect with minimal side effects, such as cardiovascular, respiratory, and temperature disturbances, compared to full opioid agonists or antagonists.[22][23] This is due to the bell-shaped analgesic dose-response curve and ceiling effect of buprenorphine.[23] In chronic treatment, buprenorphine almost eliminate the ability of opioid abusers to perceiving an acute injection of morphine, disrupting the reward cycle of addiction and hence opioid abuse.[23]

Varenicline

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image of CHAMPIX™(Varenicline) tablets launched by Pfizer UK[24]

Varenicline is a partial agonist at the nicotinic receptor, and the drug is used as highly effective aid for smoking cessation when the nicotine replacement therapy failed.[25] Partial agonism allows varenicline to reduce the rewarding feeling of smoking from nicotine by blocking the nicotinic receptors which inhibit the reaction that causes nicotine dependence, while lessening the withdrawal syndrome when quitting cigarettes.[26] Study shows that the mechanism greatly improves the success rate of smoking cessation in patients taking varenicline, and lowering the dose use can further decrease the chance of adverse effects.[26]


Future direction

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The unique properties of partial agonists also allows ongoing researches into their therapeutic potential to improve current medications.

Beta blockers with intrinsic sympathomimetic activity

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Beta blockers with ISA can possibly provides additional benefits other than reducing cardiac output while have safer drug profile.[4][20] Still, the clinical significance of beta blocker with ISA requires further research and they are rarely recommended as first line agents in clinical guidelines, such as for managing hypertension or heart failure.[27][28]

Serotonin 5-HT1A receptor partial agonist

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Serotonin 5-HT1A receptor partial agonist was first intended to be used as an antipsychotic drug acting on dopamine D2 receptors during its initial development.[6] Still, the drug was found to be ineffective in treating psychotic symptoms.[29] It is then found that there is an effectiveness in the treatment of generalized anxiety disorder (GAD) similar to benzodiazepines with no side effects common with benzodiazepine drugs such as sedation, physical dependence, cognitive impairment.[30] Consequently, research is currently being conducted to investigate the potential of 5-HT1A receptor partial agonists as an add-on therapy for schizophrenia symptoms.[6]

See also

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References

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  1. ^ a b c d e f g h i j k l m n o p Waller, Derek G.; Sampson, Anthony P. (2018-01-01), Waller, Derek G.; Sampson, Anthony P. (eds.), "1 - Principles of pharmacology and mechanisms of drug action", Medical Pharmacology and Therapeutics (Fifth Edition), Elsevier, pp. 3–31, doi:10.1016/b978-0-7020-7167-6.00001-4, ISBN 978-0-7020-7167-6, retrieved 2025-03-20
  2. ^ a b c Muir, William W.; Sams, Richard A. (2009-01-01), Gaynor, James S.; Muir, William W. (eds.), "7 - Pharmacologic Principles and Pain: Pharmacokinetics and Pharmacodynamics", Handbook of Veterinary Pain Management (Second Edition), Saint Louis: Mosby, pp. 113–140, doi:10.1016/b978-032304679-4.10007-3, ISBN 978-0-323-04679-4, retrieved 2025-03-20
  3. ^ a b c "Buprenorphine Education: Technical explanation of Buprenorphine mu receptor, affinity of agonist and antagonist". www.naabt.org. Archived from the original on 2024-10-03. Retrieved 2025-03-20.
  4. ^ a b c d e f g h i j k l m n o p q r s t u v w x y z aa Brunton, Laurence L.; Lazo, John S.; Parker, Keith L. (2023). Goodman & Gilman's The Pharmacological Basis of Therapeutics (14th ed.). The McGraw-Hill Companies, Inc.
  5. ^ a b c Page, Stephen W; Maddison, Jill E (2008-01-01), Maddison, JILL E; Page, STEPHEN W; Church, DAVID B (eds.), "Chapter 1 - Principles of clinical pharmacology", Small Animal Clinical Pharmacology (Second Edition), Edinburgh: W.B. Saunders, pp. 1–26, doi:10.1016/b978-070202858-8.50003-8, ISBN 978-0-7020-2858-8, retrieved 2025-03-20
  6. ^ a b c Celada, Pau; Bortolozzi, Analía; Artigas, Francesc (2013-09-01). "Serotonin 5-HT1A Receptors as Targets for Agents to Treat Psychiatric Disorders: Rationale and Current Status of Research". CNS Drugs. 27 (9): 703–716. doi:10.1007/s40263-013-0071-0. ISSN 1179-1934.
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  16. ^ "Teva Launches Generic Abilify® Tablets in the United States". www.tevapharm.com. 2015-04-28. Retrieved 2025-04-08.
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  18. ^ a b Siafis, Spyridon; Wu, Hui; Wang, Dongfang; Burschinski, Angelika; Nomura, Nobuyuki; Takeuchi, Hiroyoshi; Schneider-Thoma, Johannes; Davis, John M.; Leucht, Stefan. "Antipsychotic dose, dopamine D2 receptor occupancy and extrapyramidal side-effects: a systematic review and dose-response meta-analysis". Molecular Psychiatry. 28 (8): 3267–3277. doi:10.1038/s41380-023-02203-y. ISSN 1476-5578. PMC 10618092. PMID 37537284.
  19. ^ Kim, David D.; Barr, Alasdair M.; Lian, Lulu; Yuen, Jessica W. Y.; Fredrikson, Diane; Honer, William G.; Thornton, Allen E.; Procyshyn, Ric M. (2021-05-25). "Efficacy and tolerability of aripiprazole versus D2 antagonists in the early course of schizophrenia: a systematic review and meta-analysis". npj Schizophrenia. 7 (1): 1–9. doi:10.1038/s41537-021-00158-z. ISSN 2334-265X. PMC 8149726. PMID 34035313.
  20. ^ a b c d e Jaillon, Patrice (1990-09-25). "Relevance of intrinsic sympathomimetic activity for beta blockers". American Journal of Cardiology. 66 (9): C21 – C23. doi:10.1016/0002-9149(90)90758-S. ISSN 0002-9149. PMID 1977302.
  21. ^ Bruneau, Julie; Ahamad, Keith; Goyer, Marie-Ève; Poulin, Ginette; Selby, Peter; Fischer, Benedikt; Wild, T. Cameron; Wood, Evan (2018-03-05). "Management of opioid use disorders: a national clinical practice guideline". CMAJ. 190 (9): E247 – E257. doi:10.1503/cmaj.170958. ISSN 0820-3946. PMC 5837873. PMID 29507156.
  22. ^ a b Kumar, Rachna; Viswanath, Omar; Saadabadi, Abdolreza (2025), "Buprenorphine", StatPearls, Treasure Island (FL): StatPearls Publishing, PMID 29083570, retrieved 2025-03-29
  23. ^ a b c Virk, Michael S.; Arttamangkul, Seksiri; Birdsong, William T.; Williams, John T. (2009-06-03). "Buprenorphine Is a Weak Partial Agonist That Inhibits Opioid Receptor Desensitization". Journal of Neuroscience. 29 (22): 7341–7348. doi:10.1523/JNEUROSCI.3723-08.2009. ISSN 0270-6474. PMC 2752300. PMID 19494155.
  24. ^ "Champix | European Medicines Agency (EMA)". www.ema.europa.eu. 2006-10-11. Retrieved 2025-04-08.
  25. ^ Livingstone-Banks, Jonathan; Fanshawe, Thomas R; Thomas, Kyla H; Theodoulou, Annika; Hajizadeh, Anisa; Hartman, Lilian; Lindson, Nicola (2023-05-05). Cochrane Tobacco Addiction Group (ed.). "Nicotine receptor partial agonists for smoking cessation". Cochrane Database of Systematic Reviews. 2023 (5). doi:10.1002/14651858.CD006103.pub8. PMC 10169257. PMID 37142273.
  26. ^ a b Cahill, Kate; Lindson-Hawley, Nicola; Thomas, Kyla H; Fanshawe, Thomas R; Lancaster, Tim (2016-05-09). Cochrane Tobacco Addiction Group (ed.). "Nicotine receptor partial agonists for smoking cessation". Cochrane Database of Systematic Reviews. doi:10.1002/14651858.CD006103.pub7. PMC 6464943. PMID 27158893.
  27. ^ Whelton, Paul K.; Carey, Robert M.; Aronow, Wilbert S.; Casey, Donald E.; Collins, Karen J.; Dennison Himmelfarb, Cheryl; DePalma, Sondra M.; Gidding, Samuel; Jamerson, Kenneth A.; Jones, Daniel W.; MacLaughlin, Eric J.; Muntner, Paul; Ovbiagele, Bruce; Smith, Sidney C.; Spencer, Crystal C. (2018). "2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA Guideline for the Prevention, Detection, Evaluation, and Management of High Blood Pressure in Adults: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines". Hypertension. 71 (6): e13 – e115. doi:10.1161/HYP.0000000000000065.
  28. ^ Heidenreich, Paul A.; Bozkurt, Biykem; Aguilar, David; Allen, Larry A.; Byun, Joni J.; Colvin, Monica M.; Deswal, Anita; Drazner, Mark H.; Dunlay, Shannon M.; Evers, Linda R.; Fang, James C.; Fedson, Savitri E.; Fonarow, Gregg C.; Hayek, Salim S.; Hernandez, Adrian F. (2022-05-03). "2022 AHA/ACC/HFSA Guideline for the Management of Heart Failure: A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines". Circulation. 145 (18): e895 – e1032. doi:10.1161/CIR.0000000000001063.
  29. ^ Loane, C.; Politis, M. (2012-06-21). "Buspirone: What is it all about?". Brain Research. 1461: 111–118. doi:10.1016/j.brainres.2012.04.032. ISSN 0006-8993.
  30. ^ Huang, Xuefei; Yang, Jing; Yang, Sijin; Cao, Shousong; Qin, Dalian; Zhou, Ya; Li, Xiaoli; Ye, Yun; Wu, Jianming (2017-10-27). "Role of tandospirone, a 5-HT1A receptor partial agonist, in the treatment of central nervous system disorders and the underlying mechanisms". Oncotarget. 8 (60): 102705–102720. doi:10.18632/oncotarget.22170. ISSN 1949-2553. PMC 5731992. PMID 29254282.
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