Linked Life Data

19648470

Source:http://linkedlifedata.com/resource/pubmed/id/19648470

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
2
pubmed:dateCreated
2009-10-22
pubmed:abstractText
Gastroesophageal reflux disease (GERD) affects >10% of the Western population. Conventionally, GERD is treated by reducing gastric acid secretion, which is effective in most patients but inadequate in a significant minority. We describe a new therapeutic approach for GERD, based on inhibition of transient lower esophageal sphincter relaxation (TLESR) with a proposed peripherally acting GABA(B) receptor agonist, (R)-(3-amino-2-fluoropropyl)phosphinic acid (AZD3355). AZD3355 potently stimulated recombinant human GABA(B) receptors and inhibited TLESR in dogs, with a biphasic dose-response curve. In mice, AZD3355 produced considerably less central side effects than the prototypical GABA(B) receptor agonist baclofen but evoked hypothermia at very high doses (blocked by a GABA(B) receptor antagonist and absent in GABA(B)-/- mice). AZD3355 and baclofen differed markedly in their distribution in rat brain; AZD3355, but not baclofen, was concentrated in circumventricular organs as a result of active uptake (shown by avid intracellular sequestration) and related to binding of AZD3355 to native GABA transporters in rat cerebrocortical membranes. AZD3355 was also shown to be transported by all four recombinant human GABA transporters. AR-H061719 [(R/S)-(3-amino-2-fluoropropyl)phosphinic acid], (the racemate of AZD3355) inhibited the response of ferret mechanoreceptors to gastric distension, further supporting its peripheral site of action on TLESR. In summary, AZD3355 probably inhibits TLESR through stimulation of peripheral GABA(B) receptors and may offer a potential new approach to treatment of GERD.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Nov
pubmed:issn
1521-0103
pubmed:author
pubmed:issnType
Electronic
pubmed:volume
331
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
504-12
pubmed:dateRevised
2010-11-18
pubmed:meshHeading
pubmed-meshheading:19648470-Animals, pubmed-meshheading:19648470-Autoradiography, pubmed-meshheading:19648470-Baclofen, pubmed-meshheading:19648470-Binding, Competitive, pubmed-meshheading:19648470-Calcium, pubmed-meshheading:19648470-Dogs, pubmed-meshheading:19648470-Dose-Response Relationship, Drug, pubmed-meshheading:19648470-Esophageal Sphincter, Lower, pubmed-meshheading:19648470-Female, pubmed-meshheading:19648470-Ferrets, pubmed-meshheading:19648470-GABA Agonists, pubmed-meshheading:19648470-GABA Plasma Membrane Transport Proteins, pubmed-meshheading:19648470-GABA-B Receptor Agonists, pubmed-meshheading:19648470-Humans, pubmed-meshheading:19648470-Hypothermia, pubmed-meshheading:19648470-Membrane Potentials, pubmed-meshheading:19648470-Mice, pubmed-meshheading:19648470-Muscle Relaxation, pubmed-meshheading:19648470-Peripheral Nerves, pubmed-meshheading:19648470-Phosphinic Acids, pubmed-meshheading:19648470-Propylamines, pubmed-meshheading:19648470-Protein Binding, pubmed-meshheading:19648470-Protein Isoforms, pubmed-meshheading:19648470-Rats, pubmed-meshheading:19648470-Rats, Sprague-Dawley, pubmed-meshheading:19648470-Receptors, GABA-B, pubmed-meshheading:19648470-Vagus Nerve
pubmed:year
2009
pubmed:articleTitle
(R)-(3-amino-2-fluoropropyl) phosphinic acid (AZD3355), a novel GABAB receptor agonist, inhibits transient lower esophageal sphincter relaxation through a peripheral mode of action.
pubmed:affiliation
AstraZeneca R&D, Mölndal, Sweden. anders.lehmann@astrazeneca.com
pubmed:publicationType
Journal Article, In Vitro, Research Support, Non-U.S. Gov't