What systems can and can't do.

British Journal of Pharmacology
Terry Kenakin

Abstract

This commentary discusses a paper in this issue by Dr Jillian Baker on the antagonism of histamine H(2) receptors. It is an excellent example of the use of pharmacological principles to determine what systems can and can't do from the point of view of agonist-dependent antagonism. The most common model of antagonism, namely orthosteric, cannot discern agonist type; i.e. all agonists are blocked equally by a given orthosteric antagonist. Therefore, if quantitative assessment of antagonism unveils agonist dependence, then this is something an orthosteric mechanism cannot do and another mechanism must be considered. A simple alternative is a permissive allosteric model whereby the agonist and antagonist interact through conformational changes in the receptor protein. Under these circumstances, an agonist-antagonist dialogue can ensue whereby the nature of the agonist determines the magnitude of antagonist effect. Jillian Baker contrasts antagonist systems with historical data obtained for beta-adrenoceptors and the present data for histamine H(2) receptors where the simpler model of orthosteric antagonism suffices and thus shows how quantitative receptor pharmacology can be used to determine the molecular mechanism of antagonism.

References

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Feb 18, 2005·The Journal of Pharmacology and Experimental Therapeutics·Jillian G Baker
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Sep 1, 2005·Molecular Pharmacology·Jillian G Baker
Nov 3, 2005·Nature Reviews. Drug Discovery·Terry Kenakin
Jan 13, 2006·British Journal of Pharmacology·H P Rang
Jul 22, 2006·The Journal of Pharmacology and Experimental Therapeutics·Terry KenakinChristian Watson
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Jul 17, 2007·Trends in Pharmacological Sciences·Jillian G Baker, Stephen J Hill
Jul 17, 2007·Trends in Pharmacological Sciences·Barbara Bosier, Emmanuel Hermans
Jul 17, 2007·Trends in Pharmacological Sciences·Katie LeachArthur Christopoulos
Dec 25, 2007·British Journal of Pharmacology·J G Baker

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Citations

Oct 28, 2010·British Journal of Pharmacology·David A Hall, Christopher J Langmead
Jan 25, 2020·British Journal of Pharmacology·David B FinlayMichelle Glass
Jul 27, 2010·Molecular and Cellular Endocrinology·Nicola J SmithGraeme Milligan

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