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Titolo:
CHARACTERIZATION OF [H-3] BA-679-BR, A SLOWLY DISSOCIATING MUSCARINICANTAGONIST, IN HUMAN LUNG - RADIOLIGAND BINDING AND AUTORADIOGRAPHIC MAPPING
Autore:
HADDAD EB; MAK JCW; BARNES PJ;
Indirizzi:
NATL HEART & LUNG INST,DEPT THORAC MED,DOVEHOUSE ST LONDON SW3 6LY ENGLAND NATL HEART & LUNG INST,DEPT THORAC MED LONDON SW3 6LY ENGLAND
Titolo Testata:
Molecular pharmacology
fascicolo: 5, volume: 45, anno: 1994,
pagine: 899 - 907
SICI:
0026-895X(1994)45:5<899:CO[BAS>2.0.ZU;2-8
Fonte:
ISI
Lingua:
ENG
Soggetto:
GUINEA-PIG LUNG; RECEPTOR SUBTYPES; SELECTIVE ANTAGONISTS; MESSENGER-RNAS; AIRWAYS; CELLS; BRONCHODILATOR; HETEROGENEITY; METHOCTRAMINE; VISUALIZATION;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Science Citation Index Expanded
Science Citation Index Expanded
Citazioni:
36
Recensione:
Indirizzi per estratti:
Citazione:
E.B. Haddad et al., "CHARACTERIZATION OF [H-3] BA-679-BR, A SLOWLY DISSOCIATING MUSCARINICANTAGONIST, IN HUMAN LUNG - RADIOLIGAND BINDING AND AUTORADIOGRAPHIC MAPPING", Molecular pharmacology, 45(5), 1994, pp. 899-907

Abstract

Ba 679 BR [7(S)-(1 alpha,2 beta,4 beta,5 alpha,7 beta)-7-[(hydroxydi(2-thienyl) imethyl-3-oxa-9-azoniatricyclo[3.3.1.0(2,4)]nonane bromide]is a new long-acting muscarinic antagonist developed as a bronchodilator drug. In this study, we have evaluated its affinity, its selectivity, and the distribution of its binding sites in human lung. [H-3]Ba 679 BR binds to a homogeneous population of muscarinic receptors in human lung membranes, with affinities in the subnanomolar concentration range. Like ipratropium bromide, Ba 679 BR showed no selectivity in itsinteractions with rat cerebrocortical M(1) receptors (labeled with [H-3]telenzepine) or heart M(2) and salivary gland M(3) receptors [labeled with [N-methyl-H-3]scopolamine ([H-3]NMS)]. Ba 679 BR displayed 620-fold higher affinity, compared with ipratropium bromide. We also studied the rate of Ba 679 BR and ipratropium bromide dissociation from human lung muscarinic receptors, by monitoring [H-3]NMS association. Unlike ipratropium bromide (100 nM), which dissociated so quickly that there was little difference in the [H-3]NMS association, compared with vehicle-treated membranes, Ba 679 BR (1 nM) had a strong protective effect against [H-3]NMS binding (>70%) that lasted for 90 min. Kinetic experiments conducted with [H-3]Ba 679 BR confirmed the slow dissociation profile of this compound. The dissociation rate constant (k(-1)) for[H-3]Ba 679 BR was 3.29 +/- 0.18 x 10(-3) min(-1), correspending to ahalf-life of the complex of 212 +/- 11 min. Autoradiographic studies revealed that [3H]Ba 679 BR binding sites were densely distributed in alveolar walls and submucosal glands. These results suggest that the slow dissociation profile of Ba 679 BR from human lung muscarinic receptors might be the underlying mechanism by which this drug achieves itslong duration of action observed in functional tests.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 01/12/20 alle ore 08:26:57