Linked Life Data

15054115

Source:http://linkedlifedata.com/resource/pubmed/id/15054115

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
2
pubmed:dateCreated
2004-7-19
pubmed:abstractText
Mu opioid receptors are present throughout the central and peripheral nervous systems. Peripheral inflammation causes an increase in mu receptor levels on peripheral terminals of primary afferent neurons. Recent studies indicate that activation of peripheral mu receptors produces antihyperalgesic effects in animals and humans. Here, we describe the in vitro pharmacological and in vivo pharmacokinetic properties of a novel, highly potent, and peripherally restricted mu opioid agonist, [8-(3,3-diphenyl-propyl)-4-oxo-1-phenyl-1,3,8-triaza-spiro[4.5]dec-3-yl]-acetic acid (DiPOA). In a radioligand binding assay, DiPOA inhibited [(3)H]-diprenorphine binding to recombinant human mu receptors with a K(i) value of approximately 0.8 nM. The rank order of affinity for DiPOA binding to recombinant human opioid receptors was mu > kappa approximately ORL-1 >> delta. DiPOA showed potent agonist effects in a human mu receptor guanosine 5'-O-(3-[(35)S]thio)triphosphate functional assay, with an EC(50) value of approximately 33 nM and efficacy of approximately 85% [normalized to the mu agonist, [d-Ala2,MePhe4,Gly(ol)5]enkephalin]. Low potency agonist activity was also seen at ORL-1 and kappa receptors. DiPOA bound competitively to the opioid binding site of human mu receptors as demonstrated by a parallel rightward shift in its concentration-response curve in the presence of increasing concentrations of naltrexone. High and sustained (> or =5 h) plasma levels for DiPOA were achieved following intraperitoneal administration at 3 and 10 mg/kg; central nervous system penetration, however, was < or =4% of the plasma concentration, even at levels exceeding 1500 ng/ml. As such, DiPOA represents a systemically available, peripherally restricted small molecule mu opioid agonist that will aid in understanding the role played by mu opioid receptors in the periphery.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Aug
pubmed:issn
0022-3565
pubmed:author
pubmed:issnType
Print
pubmed:volume
310
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
783-92
pubmed:dateRevised
2006-11-15
pubmed:meshHeading
pubmed:year
2004
pubmed:articleTitle
DiPOA ([8-(3,3-diphenyl-propyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]dec-3-yl]-acetic acid), a novel, systemically available, and peripherally restricted mu opioid agonist with antihyperalgesic activity: I. In vitro pharmacological characterization and pharmacokinetic properties.
pubmed:affiliation
Department of Molecular Pharmacology, Purdue Pharma Discovery Research, 6 Cedarbrook Drive, Cranbury, NJ 08512, USA. ken.valenzano@pharma.com
pubmed:publicationType
Journal Article, Comparative Study