From "captive" agonism to insurmountable antagonism: Demonstrating the power of analytical pharmacology

Research output: Contribution to journalArticleResearchpeer-review

Abstract

1. Mathematical modelling is useful in pharmacology, allowing the investigator to obtain insights into the biological processes under study- that may not always be intuitively obvious. Examples are presented in this review using the pharmacology of the muscarinic acetylcholine receptor (mAChR) agonist xanomeline. 2. Xanomeline possesses a novel mode of action that involves persistent binding to the M1 mAChR, yielding a fraction of agonist in the receptor compartment that continually activates the receptor, despite extensive washout, as assessed in functional assays measuring the cumulative production of M1 mAChR-mediated L-[3H]-citrulline. This persistent effect was reversed by the antagonist atropine, but re-established upon the removal of atropine. Thus, xanomeline may represent the first "captive" agonist of the mAChR. 3. Atropine was equally potent at reversing the effect of persistently bound xanomeline and preventing the effect of added xanomeline. Application of standard quantitative equilibrium models of agonist-antagonist interaction to these data suggested that the interaction between xanomeline and atropine satisfied the criteria of competitivity in each case. 4. Subsequent real-time assays of M1 mAChR-mediated intracellular calcium mobilization found that atropine inhibited the effects of xanomeline in an insurmountable manner. 5. The discrepancy between the modes of antagonism in the various functional assays could be reconciled in a dynamic receptor model of antagonism within a transient response system and subsequent Monte Carlo simulations allowed for the development of an optimized analytical procedure to quantify antagonist potency under such conditions of response fade. 6. These types of studies exemplify the diagnostic and integrative features of analytical pharmacology.

Original languageEnglish
Pages (from-to)223-229
Number of pages7
JournalClinical and Experimental Pharmacology and Physiology
Volume28
Issue number3
DOIs
Publication statusPublished - 15 Mar 2001
Externally publishedYes

Keywords

  • Alzheimer's disease
  • Analytical pharmacology
  • Captive agonism
  • Mathematical modelling
  • Musearinic receptors
  • Receptor theory
  • Xanomeline

Cite this

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abstract = "1. Mathematical modelling is useful in pharmacology, allowing the investigator to obtain insights into the biological processes under study- that may not always be intuitively obvious. Examples are presented in this review using the pharmacology of the muscarinic acetylcholine receptor (mAChR) agonist xanomeline. 2. Xanomeline possesses a novel mode of action that involves persistent binding to the M1 mAChR, yielding a fraction of agonist in the receptor compartment that continually activates the receptor, despite extensive washout, as assessed in functional assays measuring the cumulative production of M1 mAChR-mediated L-[3H]-citrulline. This persistent effect was reversed by the antagonist atropine, but re-established upon the removal of atropine. Thus, xanomeline may represent the first {"}captive{"} agonist of the mAChR. 3. Atropine was equally potent at reversing the effect of persistently bound xanomeline and preventing the effect of added xanomeline. Application of standard quantitative equilibrium models of agonist-antagonist interaction to these data suggested that the interaction between xanomeline and atropine satisfied the criteria of competitivity in each case. 4. Subsequent real-time assays of M1 mAChR-mediated intracellular calcium mobilization found that atropine inhibited the effects of xanomeline in an insurmountable manner. 5. The discrepancy between the modes of antagonism in the various functional assays could be reconciled in a dynamic receptor model of antagonism within a transient response system and subsequent Monte Carlo simulations allowed for the development of an optimized analytical procedure to quantify antagonist potency under such conditions of response fade. 6. These types of studies exemplify the diagnostic and integrative features of analytical pharmacology.",
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From "captive" agonism to insurmountable antagonism : Demonstrating the power of analytical pharmacology. / Christopoulos, Arthur.

In: Clinical and Experimental Pharmacology and Physiology, Vol. 28, No. 3, 15.03.2001, p. 223-229.

Research output: Contribution to journalArticleResearchpeer-review

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