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Allosteric modulator

In pharmacology and biochemistry, allosteric modulators are a group of substances. Some of them, like benzodiazepines, are drugs.[1] A modulator binds to a site in some receptor. This site (i.e., an allosteric site) is not the same one to which an endogenous activator of the receptor would bind (i.e., an orthosteric site). This natural activator could be a neurotransmitter. Receptor activators and inactivators are called agonists. Modulators are either positive, negative or neutral. Positive types increase and negative types lower the probability that an agonist will bind to a receptor (i.e. affinity) and/or its ability to activate/inactivate the receptor (i.e. efficacy). Neutral types don't affect agonist activity, but can stop other modulators from binding to a receptor. Some modulators also work as allosteric agonists. Modulators and agonists can be called receptor ligands.[2]

The term "allosteric" derives from the Greek language. Allos means "other", and stereos, "solid" or "shape". This can be translated to "other shape", which indicates the conformational changes within receptors caused by the modulators through which the modulators affect the receptor function.[3]


In the context of modulators, affinity is the ability of a substance to bind to a receptor. Binding is not enough for activation, and the ability of a substance to activate a receptor is efficacy. If efficacy is zero, the substance is an antagonist. Receptor activators have positive efficacy and are agonists. Inactivators have negative efficacy and are inverse agonists. Latter are a subgroup of agonists. Antagonists inhibit the effects of inverse agonists and other agonists.[1]

Orthosteric agonist (A) binds to orthosteric site (B) of a receptor (E). Allosteric modulator (C) binds to allosteric site (D). Modulator increases/lowers the affinity (1) and/or efficacy (2) of an agonist. Modulator may also act as an agonist and yield an agonistic effect (3). Modulated orthosteric agonist affects the receptor (4). Receptor response (F) follows.

Allosteric modulators increase or lower affinity and/or efficacy of an agonist. A modulator may also increase affinity and lower efficacy or vice versa.[4] The site to which endogenous agonists bind to is named the orthosteric site. Modulators don't bind to this site. They bind to any other suitable sites, which are named allosteric sites.[2] Upon binding, modulators change the three-dimensional structure (i.e. conformation) of the receptor. The orthosteric site also changes, which changes the capabilities of an agonist.[4]

In practice, modulation can be complicated. A modulator may function as a partial agonist. It doesn't need the agonist it modulates to yield agonistic effects.[5] Also, modulation may not affect affinity or efficacy of different agonists equally. Even if a group of different agonists bind to the same receptor, some of the agonists might not be modulated by some modulators.[4]


A modulator can have 3 effects within a receptor. One is its capability or incapability to activate a receptor (2 possibilities). The other two are agonist affinity and efficacy. They may be increased, lowered or left unaffected (3 and 3 possibilities). This yields 17 possible modulator combinations.[4] There are 18 (=2*3*3) if neutral modulator type is also counted.

For all practical considerations, these combinations can be generalized only to 5 classes[4] and 1 neutral:

  • positive allosteric modulators (PAM) increase agonist affinity and/or efficacy.[4] Clinical examples are benzodiazepines like diazepam, alprazolam and chlordiazepoxide, which modulate GABAA-receptors, and cinacalcet, which modulates calcium-sensing receptors.[6]
    • PAM-agonists work like PAMs, but also as agonists with and without the agonists they modulate.[4]
    • PAM-antagonists work like PAMs, but also function as antagonists and lower the efficacy of the agonists they modulate.[4]
  • negative allosteric modulators (NAM) lower agonist affinity and/or efficacy.[4] Maraviroc is a medicine that modulates CCR5. Fenobam, raseglurant and dipraglurant are experimental GRM5 modulators.[6]
    • NAM-agonists work like NAMs, but also as agonists with and without the agonists they modulate.[4]
  • neutral allosteric modulators don't affect agonist activity, but bind to a receptor and prevent PAMs and other modulators from binding to the same receptor thus inhibiting their modulation.[4] Neutral modulators are also called silent allosteric modulators (SAM)[5] or neutral allosteric ligands (NAL). An example is 5-methyl-6-(phenylethynyl)-pyridine (5MPEP), a research chemical, which binds to GRM5.[7]

Interaction with agonists

Modulators that increase only the affinity of partial and full agonists allow their efficacy maximum to be reached sooner at lower agonist concentrations – i.e. the slope and plateau of a dose-response curve shift to lower concentrations.[4]

Efficacy increasing modulators increase maximum efficacy of partial agonists. Full agonists already activate receptors fully so modulators don't affect their maximum efficacy, but somewhat shift their response curves to lower agonist concentrations.[4]

Medical importance

Related receptors have orthosteric sites that are very similar in structure, as mutations within this site may especially lower receptor function. This can be harmful to organisms, so evolution doesn't often favor such changes. Allosteric sites are less important for receptor function, which is why they often have great variation between related receptors. This is why, in comparison to orthosteric drugs, allosteric drugs can be very specific, i.e. target their effects only on a very limited set of receptor types. However, such allosteric site variability occurs also between species so the effects of allosteric drugs vary greatly between species.[8]

Modulators can't turn receptors fully on or off as modulator action depends on endogenous ligands like neurotransmitters, which have limited and controlled production within body. This can lower overdose risk relative to similarly acting orthosteric drugs. It may also allow a strategy where doses large enough to saturate receptors can be taken safely to prolong the drug effects.[4]

Modulators affect the existing responses within tissues and can allow tissue specific drug targeting. This is unlike orthosteric drugs, which tend to produce a less targeted effect within body on all of the receptors they can bind to.[4]

See also


  1. ^ a b Rang HP, Ritter JM, Flower RJ, Henderson G (2016). Rang and Dale's pharmacology (8th ed.). Elsevier. pp. 6–20. ISBN 978-0-7020-5362-7.
  2. ^ a b Neubig RR, Spedding M, Kenakin T, Christopoulos A (December 2003). "International Union of Pharmacology Committee on Receptor Nomenclature and Drug Classification. XXXVIII. Update on terms and symbols in quantitative pharmacology" (PDF). Pharmacological Reviews. 55 (4): 597–606. doi:10.1124/pr.55.4.4. PMID 14657418.
  3. ^ Nelson DL, Cox MM (2008). Lehninger Principles of Biochemistry (5th ed.). W.H. Freeman. pp. 162. ISBN 978-0-7167-7108-1.
  4. ^ a b c d e f g h i j k l m n o p q r s t Kenakin TP (2017). Pharmacology in drug discovery and development: understanding drug response (2nd ed.). Academic Press. pp. 102–119. doi:10.1016/B978-0-12-803752-2.00005-3. ISBN 978-0-12-803752-2.
  5. ^ a b Stephens B, Handel TM (2013). Chemokine receptor oligomerization and allostery. Progress in Molecular Biology and Translational Science. 115. Academic Press. pp. 4–5. doi:10.1016/B978-0-12-394587-7.00009-9. ISBN 978-0-12-394587-7. PMC 4072031. PMID 23415099.
  6. ^ a b Melancon BJ, Hopkins CR, Wood MR, Emmitte KA, Niswender CM, Christopoulos A, et al. (February 2012). "Allosteric modulation of 7 transmembrane spanning receptors: theory, practice, and opportunities for CNS drug discovery". Journal of Medicinal Chemistry. 55 (4): 1445–64. doi:10.1021/jm201139r. PMC 3349997. PMID 22148748.
  7. ^ Hellyer SD, Albold S, Wang T, Chen AN, May LT, Leach K, Gregory KJ (May 2018). "5 Allosteric Ligands". Molecular Pharmacology. 93 (5): 504–514. doi:10.1124/mol.117.111518. PMID 29514854.
  8. ^ Lu S, He X, Ni D, Zhang J (July 2019). "Allosteric Modulator Discovery: From Serendipity to Structure-Based Design". Journal of Medicinal Chemistry. 62 (14): 6405–6421. doi:10.1021/acs.jmedchem.8b01749. PMID 30817889.