Linked Life Data

15044036

Source:http://linkedlifedata.com/resource/pubmed/id/15044036

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
1-3
pubmed:dateCreated
2004-3-26
pubmed:abstractText
The pharmacological profile of novel antagonists endowed with high affinity for the human tachykinin NK(2) receptor is presented. MEN13918 (Ngamma[Nalpha[Nalpha(benzo[b]thiophen-2-yl)carbonyl]-1-aminocyclohexan-1-carboxy]-d-phenylalanyl]-3-cis-aminocyclohexan-1-carboxylic-acid-N-(1S,2R)-2-aminocyclohexyl)amide trifluoroacetate salt) and MEN14268 (Nalpha[Nalpha(benzo[b]thiophen-2-yl)carbonyl)-1-aminocyclopentane-1-carboxyl]-d-phenylalanine-N-[3(morpholin-4-yl)propyl]amide trifluoroacetate salt) were more potent in blocking neurokinin A (NKA, His-Lys-Thr-Asp-Ser-Phe-Val-Gly-Leu-Met-NH(2)) induced contraction in human, which induced greater contraction in human (pK(B) 9.1 and 8.3) than rat (pK(B) 6.8 and <6) urinary bladder smooth muscle preparation in vitro. In agreement with functional data, in membrane preparations of CHO cells stably expressing the human NK(2) receptors, both MEN13918 and MEN14268 potently inhibited the binding of agonist ([(125)I]NKA, K(i) 0.2 and 2.8 nM) and antagonist ([(3)H]nepadutant, K(i) 0.1 and 2.2 nM, [(3)H]SR48968 K(i) 0.4 and 6.9 nM) radioligands. Using site-directed mutagenesis and radioligands binding we identified six residues in the transmembrane (TM) helices that are critical determinants for the studied antagonists affinity. To visualize these experimental findings, we constructed a homology model based on the X-ray crystal structure of bovine rhodopsin and suggested a possible binding mode of these newly discovered antagonist ligands to the human tackykinin NK(2) receptor. Both MEN13918 and MEN14268 bind amongst TM4 (Cys167Gly), TM5 (Tyr206Ala), TM6 (Tyr266Ala, Phe270Ala), and TM7 (Tyr289Phe, Tyr289Thr). MEN13918 and MEN14268 diverging binding profile at Y289 mutations in TM7 (Tyr289Phe, Tyr289Thr) suggests a relation of their different chemical moieties with this residue. Moreover, the different influence on binding of these two ligands by mutations located deep along the inner side of TM6 (Phe270Ala, Tyr266Ala, Trp263Ala) indicates a nonequivalent positioning, although occupying the same binding crevice. Furthermore, binding data indicate the Ile202Phe mutation, which mimics the wild-type rat NK(2) receptor sequence, as a species selectivity determinant. In summary, data with mutant receptors describe, for these new tachykinin NK(2) receptor antagonists, a binding site which is partially overlapping either with that of the cyclized peptide antagonist nepadutant (cyclo-[[Asn(beta-d-GlcNAc)-Asp-Trp-Phe-Dpr-Leu]cyclo(2beta-5beta)] or the nonpeptide antagonist SR48968 ((S)-N-methyl-N[4-(4-acetylamino-4-phenylpiperidino)-2-(3,4-dichlorophenyl)butyl]benzamide).
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Mar
pubmed:issn
0014-2999
pubmed:author
pubmed:issnType
Print
pubmed:day
19
pubmed:volume
488
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
61-9
pubmed:dateRevised
2006-11-15
pubmed:meshHeading
pubmed-meshheading:15044036-Animals, pubmed-meshheading:15044036-Benzamides, pubmed-meshheading:15044036-Binding, Competitive, pubmed-meshheading:15044036-Binding Sites, pubmed-meshheading:15044036-CHO Cells, pubmed-meshheading:15044036-Cell Membrane, pubmed-meshheading:15044036-Cricetinae, pubmed-meshheading:15044036-DNA, Complementary, pubmed-meshheading:15044036-Guinea Pigs, pubmed-meshheading:15044036-Ligands, pubmed-meshheading:15044036-Male, pubmed-meshheading:15044036-Models, Molecular, pubmed-meshheading:15044036-Muscle, Smooth, pubmed-meshheading:15044036-Muscle Contraction, pubmed-meshheading:15044036-Mutagenesis, Site-Directed, pubmed-meshheading:15044036-Peptides, Cyclic, pubmed-meshheading:15044036-Piperidines, pubmed-meshheading:15044036-Radioligand Assay, pubmed-meshheading:15044036-Rats, pubmed-meshheading:15044036-Receptors, Neurokinin-2
pubmed:year
2004
pubmed:articleTitle
Mutagenesis at the human tachykinin NK(2) receptor to define the binding site of a novel class of antagonists.
pubmed:affiliation
Department of Pharmacology, Menarini Ricerche S.p.A., Florence, Italy. smeini@menarini-ricerche.it
pubmed:publicationType
Journal Article, In Vitro