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| Predicate | Object |
|---|---|
| rdf:type | |
| lifeskim:mentions | |
| pubmed:issue |
2
|
| pubmed:dateCreated |
1996-6-27
|
| pubmed:abstractText |
We have identified and characterized a novel, potent, nonselective tachykinin receptor antagonist, MDL 105,212A [(R)-1-[2-[3-(3,4- dichlorophenyl)-1-(3,4,5-trimethoxybenzoyl)-pyrrolidin-3-yl] -ethyl]- 4-phenylpiperidine-4-carboxamide, hydrochloride]. The compound binds with low nanomolar affinity and species specificity to human NK-1 and NK-2 receptors as well as to guinea pig NK-3 receptors. In vitro functional assays are consistent with potent competitive antagonism of substance P-(SP) or neurokinin A-(NKA) induced [3H]-inositol phosphate accumulation in NK-1 or NK-2 monoreceptor cell lines with pA2 values of 8.19 and 8.67, respectively. Its ability to inhibit SP, NKA and capsaicin-mediated respiratory effects was examined in guinea pigs in vivo. MDL 105,212A attenuated SP-induced airway plasma protein extravasation (ED50 = 0.20 mg/kg, i.v.), NKA-induced respiratory collapse (ED50 = 5 mg/kg, i.v) and inhibited capsaicin-induced increases in pulmonary insufflation pressure (ED50 = 0.5 mg/kg, i.v.). Conscious guinea pigs responded to capsaicin aerosol exposure with dyspnea, coughs and gasps (significant respiratory events) and plasma protein extravasation. MDL 105,212A inhibited these responses in a dose-dependent manner after i.v. (ED50 = 5 mg/kg) or oral (ED50 = 50 mg/kg) administration. These data suggest that MDL 105,212A is a potent NK-1 and NK-2 receptor antagonist based on in vitro activity and its ability to inhibit SP and NKA mediated respiratory effects in vivo after exogenous administration or endogenous release and hence may be a useful therapeutic agent in neuroinflammatory disorders such as asthma in which a role for both tachykinins in the pathogenesis of the disease has been postulated.
|
| pubmed:language |
eng
|
| pubmed:journal | |
| pubmed:citationSubset |
IM
|
| pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/Inositol Phosphates,
http://linkedlifedata.com/resource/pubmed/chemical/Methacholine Chloride,
http://linkedlifedata.com/resource/pubmed/chemical/Neurokinin A,
http://linkedlifedata.com/resource/pubmed/chemical/Piperidines,
http://linkedlifedata.com/resource/pubmed/chemical/Pyrrolidines,
http://linkedlifedata.com/resource/pubmed/chemical/Receptors, Neurokinin-1,
http://linkedlifedata.com/resource/pubmed/chemical/Receptors, Neurokinin-2,
http://linkedlifedata.com/resource/pubmed/chemical/Substance P
|
| pubmed:status |
MEDLINE
|
| pubmed:month |
May
|
| pubmed:issn |
0022-3565
|
| pubmed:author | |
| pubmed:issnType |
Print
|
| pubmed:volume |
277
|
| pubmed:owner |
NLM
|
| pubmed:authorsComplete |
Y
|
| pubmed:pagination |
840-51
|
| pubmed:dateRevised |
2004-11-17
|
| pubmed:meshHeading |
pubmed-meshheading:8627566-Amino Acid Sequence,
pubmed-meshheading:8627566-Animals,
pubmed-meshheading:8627566-Asthma,
pubmed-meshheading:8627566-Bronchoconstriction,
pubmed-meshheading:8627566-Capillary Permeability,
pubmed-meshheading:8627566-Guinea Pigs,
pubmed-meshheading:8627566-Humans,
pubmed-meshheading:8627566-Inositol Phosphates,
pubmed-meshheading:8627566-Male,
pubmed-meshheading:8627566-Methacholine Chloride,
pubmed-meshheading:8627566-Mice,
pubmed-meshheading:8627566-Molecular Sequence Data,
pubmed-meshheading:8627566-Neurokinin A,
pubmed-meshheading:8627566-Piperidines,
pubmed-meshheading:8627566-Pyrrolidines,
pubmed-meshheading:8627566-Rats,
pubmed-meshheading:8627566-Receptors, Neurokinin-1,
pubmed-meshheading:8627566-Receptors, Neurokinin-2,
pubmed-meshheading:8627566-Respiration,
pubmed-meshheading:8627566-Species Specificity,
pubmed-meshheading:8627566-Substance P
|
| pubmed:year |
1996
|
| pubmed:articleTitle |
In vitro and in vivo characterization of MDL 105,212A, a nonpeptide NK-1/NK-2 tachykinin receptor antagonist.
|
| pubmed:affiliation |
Hoechst Marion Roussel, Cincinnati, Ohio, USA.
|
| pubmed:publicationType |
Journal Article
|