Non-competitive antagonist

The term "non-competitive antagonism" (sometimes called non-surmountable antagonists) can be used to describe two distinct phenomena: one in which the antagonist binds to the active site of the receptor, and one in which the antagonist binds to an allosteric site of the receptor.[1] While the mechanism of antagonism is different in both of these phenomena, they are both called "non-competitive" because the end-results of each are functionally very similar. Unlike competitive antagonists, which affect the amount of agonist necessary to achieve a maximal response but do not affect the magnitude of that maximal response, non-competitive antagonists reduce the magnitude of the maximum response that can be attained by any amount of agonist. This property earns them the name "non-competitive" because their effects cannot be negated, no matter how much agonist is present. In functional assays of non-competitive antagonists, depression of the maximal response of agonist dose-response curves, and in some cases, rightward shifts, is produced.[2] The rightward shift will occur as a result of a receptor reserve (also known as spare receptors)[3] and inhibition of the agonist response will only occur when this reserve is depleted.

An antagonist that binds to the active site of a receptor is said to be "non-competitive" if the bond between the active site and the antagonist is irreversible or nearly so.[1] This usage of the term "non-competitive" may not be ideal, however, since the term "irreversible competitive antagonism" may also be used to describe the same phenomenon without the potential for confusion with the second meaning of "non-competitive antagonism" discussed below.

The second form of "non-competitive antagonists" act at an allosteric site.[1] These antagonists bind to a distinctly separate binding site from the agonist, exerting their action to that receptor via the other binding site. They do not compete with agonists for binding at the active site. The bound antagonists may prevent conformational changes in the receptor required for receptor activation after the agonist binds.[4] Cyclothiazide has been shown to act as a reversible non-competitive antagonist of mGluR1 receptor.[5]

References

  1. 1 2 3 eds, David E. Golan, ed.-in-chief ; Armen H. Tashjian, Jr., deputy ed. ; Ehrin J. Armstrong, April W. Armstrong, associate (2008). Principles of pharmacology : the pathophysiologic basis of drug therapy (2nd ed.). Philadelphia, Pa., [etc.]: Lippincott Williams & Wilkins. p. 25. ISBN 978-0-7817-8355-2. Retrieved 2012-02-05.
  2. ↑ Vauquelin G, Van Liefde I, Birzbier BB, Vanderheyden PM; Van Liefde; Birzbier; Vanderheyden (2002). "New insights in insurmountable antagonism". Fundamental & clinical pharmacology 16 (4): 263–72. doi:10.1046/j.1472-8206.2002.00095.x. PMID 12570014.
  3. ↑ Stephenson RP (1997). "A modification of receptor theory. 1956". Br. J. Pharmacol. 120 (4 Suppl): 106–20; discussion 103–5. doi:10.1111/j.1476-5381.1997.tb06784.x. PMC 3224279. PMID 9142399. of the original article.
  4. ↑ D.E. Golan, A.H Tashjian Jr, E.J. Armstrong, A.W. Armstrong. (2007) Principles of Pharmacology: The Pathophysiologic Basis of Drug Therapy Lippincott Williams & Wilkins ISBN 0-7817-8355-0
  5. ↑ Surin A, Pshenichkin S, Grajkowska E, Surina E, Wroblewski JT; Pshenichkin; Grajkowska; Surina; Wroblewski (2007). "Cyclothiazide selectively inhibits mGluR1 receptors interacting with a common allosteric site for non-competitive antagonists". Neuropharmacology 52 (3): 744–54. doi:10.1016/j.neuropharm.2006.09.018. PMC 1876747. PMID 17095021.
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