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Article: Characterization of [3H]Ba 679 BR, a slowly dissociating muscarinic antagonist, in human lung: Radioligand binding and autoradiographic mapping

TitleCharacterization of [3H]Ba 679 BR, a slowly dissociating muscarinic antagonist, in human lung: Radioligand binding and autoradiographic mapping
Authors
Issue Date1994
PublisherAmerican Society for Pharmacology and Experimental Therapeutics. The Journal's web site is located at http://www.molpharm.org
Citation
Molecular Pharmacology, 1994, v. 45 n. 5, p. 899-907 How to Cite?
AbstractBa 679 BR [7(S)-(1α,2β,4β,5α,7β)-7-[(hydroxydi(2- thienyl)acetyl)oxy]-9,9-dimethyl-3-oxa-9-azoniatricyclo[3.3.1.02,4]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. [3H]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 its interactions with rat cerebrocortical M1 receptors (labeled with [3H]telenzepine) or heart M2 and salivary gland M3 receptors [labeled with [N-methyl-3H]scopolamine ([3H]NMS)]. Ba 679 BR displayed 6-20-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 [3H]NMS association. Unlike ipratropium bromide (100 nM), which dissociated so quickly that there was little difference in the [3H]NMS association, compared with vehicle-treated membranes, Ba 679 BR (1 nM) had a strong protective effect against [3H]NMS binding (>70%) that lasted for 90 min. Kinetic experiments conducted with [3H]Ba 679 BR confirmed the slow dissociation profile of this compound. The dissociation rate constant (k- 1) for [3H]Ba 679 BR was 3.29 ± 0.18 x 10-3 min-1, corresponding to a half-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 its long duration of action observed in functional tests.
Persistent Identifierhttp://hdl.handle.net/10722/162040
ISSN
2015 Impact Factor: 3.931
2015 SCImago Journal Rankings: 2.047
ISI Accession Number ID

 

DC FieldValueLanguage
dc.contributor.authorHaddad, EBen_US
dc.contributor.authorMak, JCWen_US
dc.contributor.authorBarnes, PJen_US
dc.date.accessioned2012-09-05T05:16:49Z-
dc.date.available2012-09-05T05:16:49Z-
dc.date.issued1994en_US
dc.identifier.citationMolecular Pharmacology, 1994, v. 45 n. 5, p. 899-907en_US
dc.identifier.issn0026-895Xen_US
dc.identifier.urihttp://hdl.handle.net/10722/162040-
dc.description.abstractBa 679 BR [7(S)-(1α,2β,4β,5α,7β)-7-[(hydroxydi(2- thienyl)acetyl)oxy]-9,9-dimethyl-3-oxa-9-azoniatricyclo[3.3.1.02,4]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. [3H]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 its interactions with rat cerebrocortical M1 receptors (labeled with [3H]telenzepine) or heart M2 and salivary gland M3 receptors [labeled with [N-methyl-3H]scopolamine ([3H]NMS)]. Ba 679 BR displayed 6-20-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 [3H]NMS association. Unlike ipratropium bromide (100 nM), which dissociated so quickly that there was little difference in the [3H]NMS association, compared with vehicle-treated membranes, Ba 679 BR (1 nM) had a strong protective effect against [3H]NMS binding (>70%) that lasted for 90 min. Kinetic experiments conducted with [3H]Ba 679 BR confirmed the slow dissociation profile of this compound. The dissociation rate constant (k- 1) for [3H]Ba 679 BR was 3.29 ± 0.18 x 10-3 min-1, corresponding to a half-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 its long duration of action observed in functional tests.en_US
dc.languageengen_US
dc.publisherAmerican Society for Pharmacology and Experimental Therapeutics. The Journal's web site is located at http://www.molpharm.orgen_US
dc.relation.ispartofMolecular Pharmacologyen_US
dc.subject.meshAdolescenten_US
dc.subject.meshAdulten_US
dc.subject.meshAnimalsen_US
dc.subject.meshAutoradiographyen_US
dc.subject.meshBinding, Competitiveen_US
dc.subject.meshBronchodilator Agents - Metabolismen_US
dc.subject.meshCerebral Cortex - Metabolismen_US
dc.subject.meshFemaleen_US
dc.subject.meshHumansen_US
dc.subject.meshLung - Metabolismen_US
dc.subject.meshMaleen_US
dc.subject.meshMyocardium - Metabolismen_US
dc.subject.meshParasympatholytics - Metabolismen_US
dc.subject.meshRadioligand Assayen_US
dc.subject.meshRatsen_US
dc.subject.meshRats, Wistaren_US
dc.subject.meshReceptors, Muscarinic - Metabolismen_US
dc.subject.meshSalivary Glands - Metabolismen_US
dc.subject.meshScopolamine Derivatives - Metabolismen_US
dc.titleCharacterization of [3H]Ba 679 BR, a slowly dissociating muscarinic antagonist, in human lung: Radioligand binding and autoradiographic mappingen_US
dc.typeArticleen_US
dc.identifier.emailMak, JCW:judymak@hku.hken_US
dc.identifier.authorityMak, JCW=rp00352en_US
dc.description.naturelink_to_subscribed_fulltexten_US
dc.identifier.pmid8190106en_US
dc.identifier.scopuseid_2-s2.0-0028179195en_US
dc.identifier.volume45en_US
dc.identifier.issue5en_US
dc.identifier.spage899en_US
dc.identifier.epage907en_US
dc.identifier.isiWOS:A1994NM73800012-
dc.publisher.placeUnited Statesen_US
dc.identifier.scopusauthoridHaddad, EB=7102803008en_US
dc.identifier.scopusauthoridMak, JCW=7103323094en_US
dc.identifier.scopusauthoridBarnes, PJ=36064679400en_US

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