Anagonistis a chemical that activates areceptorto produce a biological response. Receptors arecellularproteinswhose activation causes the cell to modify what it is currently doing. In contrast, anantagonistblocks the action of the agonist, while aninverse agonistcauses an action opposite to that of the agonist.
Etymology
editFrom theGreekαγωνιστής(agōnistēs), contestant; champion; rival <αγων(agōn), contest, combat; exertion, struggle <αγω(agō), I lead, lead towards, conduct; drive
Types of agonists
editReceptorscan be activated by eitherendogenousagonists (such ashormonesandneurotransmitters) orexogenousagonists (such asdrugs), resulting in a biological response. Aphysiological agonistis a substance that creates the same bodily responses but does not bind to the same receptor.
- Anendogenous agonistfor a particular receptor is a compound naturally produced by the body that binds to and activates that receptor. For example, the endogenous agonist forserotonin receptorsisserotonin,and the endogenous agonist fordopamine receptorsisdopamine.[1]
- Full agonistsbind to and activate a receptor with the maximum response that an agonist can elicit at the receptor. One example of a drug that can act as a full agonist isisoproterenol,which mimics the action ofadrenalineatβ adrenoreceptors.Another example ismorphine,which mimics the actions ofendorphinsatμ-opioid receptorsthroughout thecentral nervous system.However, a drug can act as a full agonist in some tissues and as a partial agonist in other tissues, depending upon the relative numbers of receptors and differences in receptor coupling.[medical citation needed]
- Aco-agonistworks with other co-agonists to produce the desired effect together.NMDA receptoractivation requires the binding of bothglutamate,glycineand D-serine co-agonists.Calciumcan also act as a co-agonist at theIP3 receptor.
- Aselective agonistis selective for a specific type of receptor. E.g.buspironeis a selective agonist for serotonin 5-HT1A.
- Partial agonists(such asbuspirone,aripiprazole,buprenorphine,ornorclozapine) also bind and activate a given receptor, but have only partialefficacyat the receptor relative to a full agonist, even at maximal receptor occupancy. Agents likebuprenorphineare used to treatopiatedependence for this reason, as they produce milder effects on the opioid receptor with lower dependence and abuse potential.
- Aninverse agonistis an agent that binds to the same receptor binding-site as an agonist for that receptor and inhibits the constitutive activity of the receptor.Inverse agonistsexert the opposite pharmacological effect of a receptor agonist, not merely an absence of the agonist effect as seen with anantagonist.An example is the cannabinoid inverse agonistrimonabant.
- Asuperagonistis a term used by some to identify a compound that is capable of producing a greater response than theendogenous agonistfor the target receptor. It might be argued that the endogenous agonist is simply a partial agonist in that tissue.
- Anirreversible agonistis a type of agonist that binds permanently to a receptor through the formation of covalent bonds.[2][3]
- Abiased agonistis an agent that binds to a receptor without affecting the same signal transduction pathway.Oliceridineis a μ-opioid receptor agonist that has been described to be functionally selective towards G protein and away from β-arrestin2 pathways.[4]
New findings that broaden the conventional definition of pharmacology demonstrate thatligandscan concurrently behave as agonistandantagonists at the same receptor, depending on effector pathways or tissue type. Terms that describe this phenomenon are "functional selectivity","protean agonism ",[5][6][7]orselective receptor modulators.[8]
Mechanism of action
editAs mentioned above, agonists have the potential to bind in different locations and in different ways depending on the type of agonist and the type of receptor.[9]The process of binding is unique to the receptor-agonist relationship, but binding induces a conformational change and activates the receptor.[9][10]This conformational change is often the result of small changes inchargeor changes inprotein foldingwhen the agonist is bound.[10][11]Two examples that demonstrate this process are themuscarinic acetylcholine receptorandNMDA receptorand their respective agonists.
For themuscarinic acetylcholine receptor,which is aG protein-coupled receptor[10](GPCR), theendogenous agonistisacetylcholine.The binding of thisneurotransmittercauses the conformational changes that propagate a signal into the cell.[10]The conformational changes are the primary effect of the agonist, and are related to the agonist's binding affinity and agonistefficacy.[9][12]Other agonists that bind to this receptor will fall under one of the different categories of agonist mentioned above based on their specific binding affinity and efficacy.
TheNMDA receptoris an example of an alternate mechanism of action, as the NMDA receptor requires co-agonists for activation. Rather than simply requiring a single specific agonist, the NMDA receptor requires both theendogenous agonists,N-methyl-D-aspartate(NMDA) andglycine.[11]These co-agonists are both required to induce the conformational change needed for the NMDA receptor to allow flow through theion channel,in this case calcium.[11]An aspect demonstrated by the NMDA receptor is that the mechanism or response of agonists can be blocked by a variety of chemical and biological factors.[11]NMDA receptors specifically are blocked by amagnesiumion unless the cell is also experiencingdepolarization.[11]
These differences show that agonists have unique mechanisms of action depending on the receptor activated and the response needed.[9][10]The goal and process remains generally consistent however, with the primary mechanism of action requiring the binding of the agonist and the subsequent changes in conformation to cause the desired response at the receptor.[9][12]This response as discussed above can vary from allowing flow ofionsto activating aGPCRand transmitting a signal into thecell.[9][10]
Activity
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Potency
editPotency is the amount of agonist needed to elicit a desired response. Thepotencyof an agonist is inversely related to itshalf maximal effective concentration(EC50) value. The EC50can be measured for a given agonist by determining the concentration of agonist needed to elicit half of the maximum biological response of the agonist. The EC50value is useful for comparing the potency of drugs with similarefficaciesproducing physiologically similar effects. The smaller the EC50value, the greater the potency of the agonist, the lower the concentration of drug that is required to elicit the maximum biological response.
Therapeutic index
editWhen a drug is used therapeutically, it is important to understand the margin of safety that exists between the dose needed for the desired effect and the dose that produces unwanted and possibly dangerous side-effects (measured by the TD50,the dose that produces toxicity in 50% of individuals). This relationship, termed thetherapeutic index,is defined as the ratioTD50:ED50.In general, the narrower this margin, the more likely it is that the drug will produce unwanted effects. The therapeutic index emphasizes the importance of the margin of safety, as distinct from the potency, in determining the usefulness of a drug.
See also
editReferences
edit- ^Goodman and Gilman's Manual of Pharmacology and Therapeutics. (11th edition, 2008). p14.ISBN0-07-144343-6
- ^De Mey JGR, Compeer MG, Meens MJ (2009). "Endothelin-1, an Endogenous Irreversible Agonist in Search of an Allosteric Inhibitor".Mol Cell Pharmacol.1(5): 246–257.
- ^Rosenbaum DM, Zhang C, Lyons JA, Holl R, Aragao D, Arlow DH, et al. (January 2011)."Structure and function of an irreversible agonist-β(2) adrenoceptor complex".Nature.469(7329): 236–240.Bibcode:2011Natur.469..236R.doi:10.1038/nature09665.PMC3074335.PMID21228876.
- ^DeWire SM, Yamashita DS, Rominger DH, Liu G, Cowan CL, Graczyk TM, et al. (March 2013). "A G protein-biased ligand at the μ-opioid receptor is potently analgesic with reduced gastrointestinal and respiratory dysfunction compared with morphine".The Journal of Pharmacology and Experimental Therapeutics.344(3): 708–717.doi:10.1124/jpet.112.201616.PMID23300227.S2CID8785003.
- ^Kenakin T (March 2001)."Inverse, protean, and ligand-selective agonism: matters of receptor conformation".FASEB Journal.15(3): 598–611.CiteSeerX10.1.1.334.8525.doi:10.1096/fj.00-0438rev.PMID11259378.S2CID18260817.
- ^Urban JD, Clarke WP, von Zastrow M, Nichols DE, Kobilka B, Weinstein H, et al. (January 2007)."Functional selectivity and classical concepts of quantitative pharmacology".The Journal of Pharmacology and Experimental Therapeutics.320(1): 1–13.doi:10.1124/jpet.106.104463.PMID16803859.S2CID447937.
- ^De Min A, Matera C, Bock A, Holze J, Kloeckner J, Muth M, et al. (April 2017)."A New Molecular Mechanism To Engineer Protean Agonism at a G Protein-Coupled Receptor".Molecular Pharmacology.91(4): 348–356.doi:10.1124/mol.116.107276.PMID28167741.
- ^Smith CL, O'Malley BW (February 2004)."Coregulator function: a key to understanding tissue specificity of selective receptor modulators".Endocrine Reviews.25(1): 45–71.doi:10.1210/er.2003-0023.PMID14769827.
- ^abcdefColquhoun D (January 2006)."Agonist-activated ion channels".British Journal of Pharmacology.147(S1): S17–S26.doi:10.1038/sj.bjp.0706502.PMC1760748.PMID16402101.
- ^abcdefKruse AC, Ring AM, Manglik A, Hu J, Hu K, Eitel K, et al. (December 2013)."Activation and allosteric modulation of a muscarinic acetylcholine receptor".Nature.504(7478): 101–106.Bibcode:2013Natur.504..101K.doi:10.1038/nature12735.PMC4020789.PMID24256733.
- ^abcdeZhu S, Stein RA, Yoshioka C, Lee CH, Goehring A, Mchaourab HS, Gouaux E (April 2016)."Mechanism of NMDA Receptor Inhibition and Activation".Cell.165(3): 704–714.doi:10.1016/j.cell.2016.03.028.PMC4914038.PMID27062927.
- ^abStrange PG (April 2008)."Agonist binding, agonist affinity and agonist efficacy at G protein-coupled receptors".British Journal of Pharmacology.153(7): 1353–1363.doi:10.1038/sj.bjp.0707672.PMC2437915.PMID18223670.