Linked Life Data

10691683

Source:http://linkedlifedata.com/resource/pubmed/id/10691683

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
4
pubmed:dateCreated
2000-3-16
pubmed:abstractText
Topographically constrained analogues of the highly mu-opioid-receptor-selective antagonist CTAP (H-D-Phe-c[Cys-Tyr-D-Trp-Arg-Thr-Pen]-Thr-NH(2), 1) were prepared by solid-phase peptide synthesis. Replacement of the D-Phe residue with conformationally biased beta-methyl derivatives of phenylalanine or tryptophan (2R,3R; 2R,3S; 2S,3R; 2S,3S) yielded peptides that displayed widely varying types of biological activities. In an effort to correlate the observed biological activities of these analogues with their structures, two-dimensional (1)H NMR and molecular modeling was performed. Unlike the parent (1), which is essentially a pure mu antagonist with weak delta agonist activities in the MVD bioassay, the diastereomeric beta-MePhe(1)-containing peptides exhibited simultaneous delta agonism and mu antagonism by the (2R,3R)-containing isomer 2; mu antagonism by the (2R,3S)-containing isomer 3; weak mu agonism by the (2S,3R)-containing isomer 4; and delta agonism by the (2S,3S)-containing isomer 5. Incorporation of beta-MeTrp isomers into position 1 led to peptides that were mu antagonists (2R,3R), 8; (2R,3S), 9, or essentially inactive (<10%) in the MVD and GPI assays (2S,3R), 10; (2S,3S), 11. Interestingly, in vivo antinociceptive activity was predicted by neither MVD nor GPI bioactivity. When D-Trp was incorporated in position 1, the result (7) is a partial, yet relatively potent mu agonist which also displayed weak delta agonist activity. Molecular modeling based on 2D NMR revealed that low energy conformers of peptides with similar biological activities had similar aromatic pharmacophore orientations and interaromatic distances. Peptides that exhibit mu antagonism have interaromatic distances of 7.0-7.9 A and have their amino terminal aromatic moiety pointing in a direction opposite to the direction that the amino terminus points. Peptides with delta opioid activity displayed an interaromatic distance of <7 A and had their amino terminal aromatic moiety pointing in the same direction as the amino terminus.
pubmed:grant
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Feb
pubmed:issn
0022-2623
pubmed:author
pubmed:issnType
Print
pubmed:day
24
pubmed:volume
43
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
569-80
pubmed:dateRevised
2008-11-21
pubmed:meshHeading
pubmed-meshheading:10691683-Analgesics, Opioid, pubmed-meshheading:10691683-Animals, pubmed-meshheading:10691683-Brain, pubmed-meshheading:10691683-Magnetic Resonance Spectroscopy, pubmed-meshheading:10691683-Male, pubmed-meshheading:10691683-Mice, pubmed-meshheading:10691683-Mice, Inbred ICR, pubmed-meshheading:10691683-Models, Molecular, pubmed-meshheading:10691683-Narcotic Antagonists, pubmed-meshheading:10691683-Pain Measurement, pubmed-meshheading:10691683-Peptide Fragments, pubmed-meshheading:10691683-Peptides, pubmed-meshheading:10691683-Radioligand Assay, pubmed-meshheading:10691683-Rats, pubmed-meshheading:10691683-Rats, Sprague-Dawley, pubmed-meshheading:10691683-Receptors, Opioid, delta, pubmed-meshheading:10691683-Receptors, Opioid, mu, pubmed-meshheading:10691683-Somatostatin, pubmed-meshheading:10691683-Stereoisomerism, pubmed-meshheading:10691683-Structure-Activity Relationship, pubmed-meshheading:10691683-Vas Deferens
pubmed:year
2000
pubmed:articleTitle
Opiate aromatic pharmacophore structure-activity relationships in CTAP analogues determined by topographical bias, two-dimensional NMR, and biological activity assays.
pubmed:affiliation
Departments of Biochemistry, Chemistry, and Pharmacology, University of Arizona, Tucson, Arizona 85721, USA.
pubmed:publicationType
Journal Article, In Vitro, Research Support, U.S. Gov't, P.H.S.