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 language | English |
|---|---|
| Pages (from-to) | 223-229 |
| Number of pages | 7 |
| Journal | Clinical and Experimental Pharmacology and Physiology |
| Volume | 28 |
| Issue number | 3 |
| DOIs | |
| Publication status | Published - 15 Mar 2001 |
| Externally published | Yes |
Keywords
- Alzheimer's disease
- Analytical pharmacology
- Captive agonism
- Mathematical modelling
- Musearinic receptors
- Receptor theory
- Xanomeline
Cite this
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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 journal › Article › Research › peer-review
TY - JOUR
T1 - From "captive" agonism to insurmountable antagonism
T2 - Demonstrating the power of analytical pharmacology
AU - Christopoulos, Arthur
PY - 2001/3/15
Y1 - 2001/3/15
N2 - 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.
AB - 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.
KW - Alzheimer's disease
KW - Analytical pharmacology
KW - Captive agonism
KW - Mathematical modelling
KW - Musearinic receptors
KW - Receptor theory
KW - Xanomeline
UR - http://www.scopus.com/inward/record.url?scp=0035123562&partnerID=8YFLogxK
U2 - 10.1046/j.1440-1681.2001.03376.x
DO - 10.1046/j.1440-1681.2001.03376.x
M3 - Article
VL - 28
SP - 223
EP - 229
JO - Clinical and Experimental Pharmacology and Physiology
JF - Clinical and Experimental Pharmacology and Physiology
SN - 0305-1870
IS - 3
ER -