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Titolo:
From 'captive' agonism to insurmountable antagonism: Demonstrating the power of analytical pharmacology
Autore:
Christopoulos, A;
Indirizzi:
Univ Melbourne, Dept Pharmacol, Parkville, Vic 3010, Australia Univ Melbourne Parkville Vic Australia 3010 arkville, Vic 3010, Australia
Titolo Testata:
CLINICAL AND EXPERIMENTAL PHARMACOLOGY AND PHYSIOLOGY
fascicolo: 3, volume: 28, anno: 2001,
pagine: 223 - 229
SICI:
0305-1870(200103)28:3<223:F'ATIA>2.0.ZU;2-T
Fonte:
ISI
Lingua:
ENG
Soggetto:
MUSCARINIC ACETYLCHOLINE-RECEPTOR; FUNCTIONAL SELECTIVITY; BEHAVIORAL SYMPTOMS; ALZHEIMER-DISEASE; XANOMELINE; INHIBITION; ACTIVATION; AFFINITY; CURVES; SCHILD;
Keywords:
Alzheimer's disease; analytical pharmacology; captive agonism; mathematical modelling; muscarinic receptors; receptor theory; xanomeline;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
35
Recensione:
Indirizzi per estratti:
Indirizzo: Christopoulos, A Univ Melbourne, Dept Pharmacol, Grattan St, Parkville, Vic 3010, Australia Univ Melbourne Grattan St Parkville Vic Australia 3010 ia
Citazione:
A. Christopoulos, "From 'captive' agonism to insurmountable antagonism: Demonstrating the power of analytical pharmacology", CLIN EXP PH, 28(3), 2001, pp. 223-229

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 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 M1mAChR-mediated L-[H-3]-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 ofstandard quantitative equilibrium models of agonist-antagonist interactionto these data suggested that the interaction between xanomeline and atropine satisfied the criteria of competitivity in each case,4. Subsequent real-time assays of MI 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.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 30/03/20 alle ore 00:48:04