Linked Life Data

10090788

Source:http://linkedlifedata.com/resource/pubmed/id/10090788

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
6
pubmed:dateCreated
1999-4-13
pubmed:abstractText
Optimization of the previously reported 2-phenyl-4-quinolinecarboxamide NK-3 receptor antagonist 14, with regard to potential metabolic instability of the ester moiety and affinity and selectivity for the human neurokinin-3 (hNK-3) receptor, is described. The ester functionality could be successfully replaced by the ketone (31) or by lower alkyl groups (Et, 21, or n-Pr, 24). Investigation of the substitution pattern of the quinoline ring resulted in the identification of position 3 as a key position to enhance hNK-3 binding affinity and selectivity for the hNK-3 versus the hNK-2 receptor. All of the chemical groups introduced at this position, with the exception of halogens, increased the hNK-3 binding affinity, and compounds 53 (3-OH, SB 223412, hNK-3-CHO binding Ki = 1.4 nM) and 55 (3-NH2, hNK-3-CHO binding Ki = 1.2 nM) were the most potent compounds of this series. Selectivity studies versus the other neurokinin receptors (hNK-2-CHO and hNK-1-CHO) revealed that 53 is about 100-fold selective for the hNK-3 versus hNK-2 receptor, with no affinity for the hNK-1 at concentrations up to 100 microM. In vitro studies demonstrated that 53 is a potent functional antagonist of the hNK-3 receptor (reversal of senktide-induced contractions in rabbit isolated iris sphincter muscles and reversal of NKB-induced Ca2+ mobilization in CHO cells stably expressing the hNK-3 receptor), while in vivo this compound showed oral and intravenous activity in NK-3 receptor-driven models (senktide-induced behavioral responses in mice and senktide-induced miosis in rabbits). Overall, the biological data indicate that (S)-N-(1-phenylpropyl)-3-hydroxy-2-phenylquinoline-4-carboxamide (53, SB 223412) may serve as a pharmacological tool in animal models of disease to assess the functional and pathophysiological role of the NK-3 receptor and to establish therapeutic indications for non-peptide NK-3 receptor antagonists.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Mar
pubmed:issn
0022-2623
pubmed:author
pubmed:issnType
Print
pubmed:day
25
pubmed:volume
42
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
1053-65
pubmed:dateRevised
2006-11-15
pubmed:meshHeading
pubmed-meshheading:10090788-Animals, pubmed-meshheading:10090788-CHO Cells, pubmed-meshheading:10090788-Calcium, pubmed-meshheading:10090788-Cell Line, pubmed-meshheading:10090788-Cloning, Molecular, pubmed-meshheading:10090788-Cricetinae, pubmed-meshheading:10090788-Humans, pubmed-meshheading:10090788-Iris, pubmed-meshheading:10090788-Mice, pubmed-meshheading:10090788-Miosis, pubmed-meshheading:10090788-Motor Activity, pubmed-meshheading:10090788-Muscle, Smooth, pubmed-meshheading:10090788-Muscle Contraction, pubmed-meshheading:10090788-Peptide Fragments, pubmed-meshheading:10090788-Quinolines, pubmed-meshheading:10090788-Rabbits, pubmed-meshheading:10090788-Radioligand Assay, pubmed-meshheading:10090788-Receptors, Neurokinin-3, pubmed-meshheading:10090788-Structure-Activity Relationship, pubmed-meshheading:10090788-Substance P
pubmed:year
1999
pubmed:articleTitle
Discovery of a novel class of selective non-peptide antagonists for the human neurokinin-3 receptor. 2. Identification of (S)-N-(1-phenylpropyl)-3-hydroxy-2-phenylquinoline-4-carboxamide (SB 223412).
pubmed:affiliation
Department of Medicinal Chemistry, SmithKline Beecham S.p.A., Via Zambeletti, 20021 Baranzate, Milano, Italy.
pubmed:publicationType
Journal Article, In Vitro