An operational model of pharmacological agonism: the effect of E/[A] curve shape on agonist dissociation constant estimation

British Journal of Pharmacology
J W BlackJ Wood

Abstract

An operational model of pharmacological agonism has been analysed to predict the behaviour of rectangular hyperbolic and non-hyperbolic agonist-concentration effect, E/[A], curves with variation in receptor concentration, [Ro]. Irreversible antagonism is predicted to cause E/[A] curve gradient changes in non-hyperbolic cases but not in hyperbolic cases; in both cases estimation of agonist dissociation constants (KAS) is theoretically valid. 5-Hydroxytryptamine (5-HT) produced "steep' E/[A] curves in contracting the rabbit isolated aorta preparation. Irreversible antagonism by phenoxybenzamine (Pbz) produced a flattened E/[A] curve, consistent with theoretical predictions. Fitting 5-HT E/[A] curves in the presence and absence of Pbz to the model provided an estimate of KA for 5-HT which was not significantly different from the estimate obtained using Furchgott's null method. The operational model of agonism appears to account qualitatively and quantitatively for the effects of [Ro] changes on hyperbolic and non-hyperbolic E/[A] curves. Under conditions where irreversible antagonism may be used to estimate KAS, fitting the operational model directly to E/[A] data represents a valid, economical and analytically simple alternative ...Continue Reading

References

Oct 1, 1976·British Journal of Pharmacology·E ApperleyG P Levy
Dec 22, 1983·Proceedings of the Royal Society of London. Series B, Containing Papers of a Biological Character·J W Black, P Leff
Jun 1, 1984·British Journal of Pharmacology·E KrstewC Raper
Dec 1, 1956·British Journal of Pharmacology and Chemotherapy·R P STEPHENSON
Dec 1, 1962·British Journal of Pharmacology and Chemotherapy·I R INNES
Apr 1, 1965·British Journal of Pharmacology and Chemotherapy·W D PATON, A M ROTHSCHILD

Citations

Aug 1, 1990·Naunyn-Schmiedeberg's Archives of Pharmacology·S J MacLennan, G R Martin
Apr 1, 1989·In Vitro Cellular & Developmental Biology : Journal of the Tissue Culture Association·J W Black
Feb 7, 2008·Naunyn-Schmiedeberg's Archives of Pharmacology·Frederick J Ehlert
Jun 15, 1990·Biochemical Pharmacology·J GuiramandM Récasens
Jun 27, 1996·European Journal of Pharmacology·A M GabilondoMartin J Lohse
May 1, 1990·Journal of Pharmacological Methods·P LeffJ Wood
Nov 1, 1988·Trends in Pharmacological Sciences·P Leff
Jun 1, 1996·Trends in Pharmacological Sciences·M CorsiD G Trist
Dec 21, 2002·Life Sciences·F Borrelli, I A Tavares
Dec 16, 1998·Trends in Pharmacological Sciences·J Giraldo
Nov 1, 2001·Journal of Pharmacological and Toxicological Methods·E E DanielL Janssen
Apr 1, 1997·Journal of Pharmacological and Toxicological Methods·C ScaramelliniP Leff
Dec 22, 1999·Journal of Pharmacological and Toxicological Methods·P H Van der Graaf, R C Schoemaker
Aug 4, 2012·ACS Chemical Neuroscience·Terry KenakinSteven Novick
Feb 16, 2013·Nature Reviews. Drug Discovery·Terry Kenakin, Arthur Christopoulos
May 18, 2013·Nature Reviews. Drug Discovery·Terry Kenakin, Arthur Christopoulos
Jun 18, 1998·British Journal of Pharmacology·M S FaguraP Leff
Dec 1, 1992·British Journal of Pharmacology·M I ChristieG W Smith
Aug 21, 2013·Biochemical Pharmacology·Terry Kenakin, Michael Williams
Nov 14, 1997·Proceedings of the National Academy of Sciences of the United States of America·A M GabilondoMartin J Lohse
Jul 22, 2014·Trends in Pharmacological Sciences·Terry Kenakin
Mar 29, 1994·Proceedings of the National Academy of Sciences of the United States of America·G PeiR J Lefkowitz
Sep 17, 1996·Proceedings of the National Academy of Sciences of the United States of America·J TurkiS B Liggett
Oct 21, 2009·The Journal of Pharmacology and Experimental Therapeutics·Gregory W SawyerCrystal A Shults
Jan 1, 2013·In Silico Pharmacology·Masoud JameiAmin Rostami-Hodjegan
Jul 16, 2010·Nihon yakurigaku zasshi. Folia pharmacologica Japonica·Masayuki YamadaChikuma Hamada
May 1, 2015·Expert Opinion on Drug Discovery·Rumin Zhang, Michael Kavana
Feb 10, 2016·Chemical Reviews·Terry Kenakin
Mar 19, 2011·Journal of Molecular Graphics & Modelling·Fabio LannuttiNazzareno Re
Oct 28, 2015·British Journal of Clinical Pharmacology·Terry Kenakin
Dec 27, 2008·Pharmacology & Therapeutics·V J AloyoJ A Harvey
Sep 16, 2008·European Journal of Pharmacology·Priyank KumarByron C Yoburn
Sep 2, 2004·British Journal of Pharmacology·Pieter JanssenRomain A Lefebvre
Nov 16, 2005·Statistics in Medicine·Attila Frigyesi, Ola Hössjer
Sep 22, 2012·British Journal of Pharmacology·Terry Kenakin
Mar 1, 1989·British Journal of Pharmacology·P Leff, I G Dougall
Sep 15, 2015·Methods : a Companion to Methods in Enzymology·Karim Nagi, Graciela Pineyro
Apr 17, 2015·Neuropsychopharmacology : Official Publication of the American College of Neuropsychopharmacology·J Elliott RobinsonC J Malanga
Mar 25, 2011·Trends in Pharmacological Sciences·Jillian G BakerRoger J Summers
Jul 22, 2008·Pharmacology, Biochemistry, and Behavior·Sunil SirohiByron C Yoburn
Sep 8, 2016·Biophysical Journal·Stuart J Edelstein, Jean-Pierre Changeux
Jan 20, 2017·ACS Chemical Neuroscience·Robert B LaprairieGanesh A Thakur
Mar 10, 2017·Expert Opinion on Drug Discovery·Terry Kenakin
Nov 15, 2017·Scientific Reports·Javier BurgueñoJesus Giraldo
Mar 3, 2018·British Journal of Pharmacology·David A Hall, J Giraldo
Apr 1, 1988·Medicinal Research Reviews·P Leff, G R Martin
May 30, 1997·Annals of the New York Academy of Sciences·M Spedding, C Dacquet
Aug 19, 2017·Nature Chemical Biology·J Robert LaneArthur Christopoulos
May 18, 2019·International Journal of Molecular Sciences·Julie SanchezMartin J Stone
Jan 10, 2018·The Journal of Pharmacology and Experimental Therapeutics·Carol A ParonisJack Bergman
Mar 28, 2019·Pharmacological Reviews·Terry Kenakin
Dec 19, 2018·Pharmacological Reviews·R Kyle Palmer
Jul 3, 2015·Molecular Pharmacology·Louis M LuttrellLaura M Bohn
Mar 2, 2012·Molecular Pharmacology·Manuela Ambrosio, Martin J Lohse
Jun 22, 1990·Proceedings of the Royal Society of London. Series B, Containing Papers of a Biological Character·J W Black, N P Shankley
May 17, 2014·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Oualid SbaiPhilippe Rondard
Jan 25, 2020·British Journal of Pharmacology·David B FinlayMichelle Glass
Jan 18, 2014·Molecular Endocrinology·Louis M Luttrell
Sep 5, 2019·Scientific Reports·Nyantsz WuMichael P Maher
Sep 14, 1999·British Journal of Pharmacology·J R RaymondM N Garnovskaya
Mar 1, 1986·British Journal of Pharmacology·V J BarrettP J Richardson
Jan 5, 2002·Journal of Receptor and Signal Transduction Research·L G Dougall
Mar 18, 2017·Current Protocols in Pharmacology·Terry Kenakin
Dec 1, 1987·British Journal of Pharmacology·I G Dougall, P Leff
Jul 10, 2014·The Journal of Biological Chemistry·Peter KeovArthur Christopoulos
Jan 18, 2017·Pharmacology Research & Perspectives·Verena GottaP H Van der Graaf
May 1, 1996·British Journal of Pharmacology·P H Van der GraafJ W Black
Nov 14, 2018·Scientific Reports·Harvey G RowethGavin E Jarvis
Sep 1, 2018·Translational and Clinical Pharmacology·Hyungsub Kim, Hyeong-Seok Lim
Oct 16, 2019·Proceedings of the National Academy of Sciences of the United States of America·Jinsai ShangDouglas J Kojetin
Jul 1, 1987·The American Journal of Physiology·L D Homer, T B Nielsen
Sep 17, 2016·Current Protocols in Pharmacology·Terry Kenakin
Jul 30, 2019·Journal of Theoretical Biology·Terry Kenakin
Feb 20, 2021·Cellular Signalling·H Ongun Onaran, Tommaso Costa
Jan 21, 2021·The Journal of Pharmacology and Experimental Therapeutics·R Kyle PalmerJohn Talley
Feb 18, 2016·European Neuropsychopharmacology : the Journal of the European College of Neuropsychopharmacology·Alexandra KaufmannAlex Hofer
May 1, 2021·International Journal of Molecular Sciences·Herman D LimMartin J Stone

Related Concepts

Metazoa
Descending Aorta
Drug Formulation Process
Drug Antagonism
Muscle, Smooth, Vascular
Phenoxybenzamine Hydrochloride
Chinchilla Rabbits
Receptors, Drug
Hydroxytryptamine
In Vitro [Publication Type]

Trending Feeds

COVID-19

Coronaviruses encompass a large family of viruses that cause the common cold as well as more serious diseases, such as the ongoing outbreak of coronavirus disease 2019 (COVID-19; formally known as 2019-nCoV). Coronaviruses can spread from animals to humans; symptoms include fever, cough, shortness of breath, and breathing difficulties; in more severe cases, infection can lead to death. This feed covers recent research on COVID-19.

Evolution of Pluripotency

Pluripotency refers to the ability of a cell to develop into three primary germ cell layers of the embryo. This feed focuses on the mechanisms that underlie the evolution of pluripotency. Here is the latest research.

Lipidomics & Rhinovirus Infection

Lipidomics can be used to examine the lipid species involved with pathogenic conditions, such as viral associated inflammation. Discovered the latest research on Lipidomics & Rhinovirus Infection.

Alzheimer's Disease: MS4A

Variants within the membrane-spanning 4-domains subfamily A (MS4A) gene cluster have recently been implicated in Alzheimer's disease in genome-wide association studies. Here is the latest research on Alzheimer's disease and MS4A.

Chronic Fatigue Syndrome

Chronic fatigue syndrome is a disease characterized by unexplained disabling fatigue; the pathology of which is incompletely understood. Discover the latest research on chronic fatigue syndrome here.

Torsion Dystonia

Torsion dystonia is a movement disorder characterized by loss of control of voluntary movements appearing as sustained muscle contractions and/or abnormal postures. Here is the latest research.

Generating Insulin-Secreting Cells

Reprogramming cells or using induced pluripotent stem cells to generate insulin-secreting cells has significant therapeutic implications for diabetics. Here is the latest research on generation of insulin-secreting cells.

Central Pontine Myelinolysis

Central Pontine Myelinolysis is a neurologic disorder caused most frequently by rapid correction of hyponatremia and is characterized by demyelination that affects the central portion of the base of the pons. Here is the latest research on this disease.

Epigenome Editing

Epigenome editing is the directed modification of epigenetic marks on chromatin at specified loci. This tool has many applications in research as well as in the clinic. Find the latest research on epigenome editing here.