Linked Life Data

19954245

Source:http://linkedlifedata.com/resource/pubmed/id/19954245

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
23
pubmed:dateCreated
2009-12-3
pubmed:abstractText
In previous structure-activity relationship (SAR) studies, (3R)-7-hydroxy-N-[(1S)-1-{[(3R,4R)-4-(3-hydroxyphenyl)-3,4-dimethyl-1-piperidinyl]methyl}-2-methylpropyl]-1,2,3,4-tetrahydro-3-isoquinolinecarboxamide (JDTic, 3) was identified as the first potent and selective kappa-opioid receptor antagonist from the trans-3,4-dimethyl-4-(3-hydroxyphenyl)piperidine class of opioid antagonists. In the present study, we report the synthesis of analogues 8a-p of 3 and present their in vitro opioid receptor functional antagonism using a [(35)S]GTPgammaS binding assay. Compounds 8a-p are analogues of 3 containing one, two, or three methyl groups connected to the JDTic structure at five different positions. All the analogues with one and two added methyl groups with the exception of 8k had subnanomolar K(e) values at the kappa receptor. The three most potent analogues were the monomethylated (3R)-7-hydroxy-N-[(1S,2S)-1-{[(3R,4R)-4-(3-hydroxyphenyl)-3,4-dimethylpiperidine-1-yl]methyl}-2-methylbutyl]-1,2,3,4-tetrahydroisoquinoline-3-carboxamide (8a) and (3R)-7-hydroxy-N-[(1S)-1-{[(3R,4R)-4-(3-hydroxyphenyl)-3,4-dimethylpiperidin-1-yl]methyl}-(2-methylpropyl)]-3-methyl-1,2,3,4-tetrahydroisoquinoline-3-carboxamide (8e) with K(e) values of 0.03 nM at the kappa receptor and (3R)-7-hydroxy-N-[(1S)-1-{[(3R,4R)-4-(3-methoxyphenyl)-3,4-dimethylpiperidin-1-yl]methyl}-2-methylpropyl]-1,2,3,4-tetrahydroisoquinoline-3-carboxamide (8d) with K(e) = 0.037 nM at the kappa receptor. All three compounds were selective for the kappa receptor relative to the micro and delta receptors. Overall, the results from this study highlight those areas that are tolerant to substitution on 3.
pubmed:grant
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Dec
pubmed:issn
1520-4804
pubmed:author
pubmed:issnType
Electronic
pubmed:day
10
pubmed:volume
52
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
7463-72
pubmed:meshHeading
pubmed:year
2009
pubmed:articleTitle
Synthesis and in vitro opioid receptor functional antagonism of methyl-substituted analogues of (3R)-7-hydroxy-N-[(1S)-1-{[(3R,4R)-4-(3-hydroxyphenyl)-3,4-dimethyl-1-piperidinyl]methyl}-2-methylpropyl]-1,2,3,4-tetrahydro-3-isoquinolinecarboxamide (JDTic).
pubmed:affiliation
Center for Organic and Medicinal Chemistry, Research Triangle Institute, Post Office Box 12194, Research Triangle Park, North Carolina 27709-2194, USA.
pubmed:publicationType
Journal Article, Research Support, N.I.H., Extramural