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Annual Scientific Meeting of ASCEPT, 1999 From ‘Captive’ Agonism To Insurmountable Antagonism: Demonstrating The Power Of Analytical Pharmacology
Author(s) -
Christopoulos Arthur
Publication year - 2001
Publication title -
clinical and experimental pharmacology and physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.752
H-Index - 103
eISSN - 1440-1681
pISSN - 0305-1870
DOI - 10.1046/j.1440-1681.2001.03376.x
Subject(s) - agonist , pharmacology , antagonism , atropine , antagonist , muscarinic acetylcholine receptor , chemistry , competitive antagonist , receptor , endocrinology , medicine , biochemistry
SUMMARY 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 M 1 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 M 1 mAChR‐mediated L ‐[ 3 H]‐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 M 1 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.