Source:http://linkedlifedata.com/resource/pubmed/id/10854288
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| Predicate | Object |
|---|---|
| rdf:type | |
| lifeskim:mentions | |
| pubmed:issue |
1
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| pubmed:dateCreated |
2000-7-17
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| pubmed:abstractText |
[D-Pen(2),D-Pen(5)]-Enkephalin (DPDPE) is an enzymatically stable delta-opioid receptor-selective peptide, which was modified by the trimethylation of the Phe(4) residue to give beta-methyl-2', 6'-dimethylphenylalanine (TMP), resulting in four conformations : (2R,3S)-beta-Phe-DPDPE, (2R,3R)-beta-Phe-DPDPE, (2R, 3S)-beta-Phe-DPDPE, and (2S,3R)-beta-Phe-DPDPE. Synthesis was by solid-phase techniques using enantiomerically pure amino acids to give the four optically pure diastereoisomer peptides. The potency and selectivity (delta- versus mu-opioid receptor) were evaluated by radioreceptor binding in rat brain, with a mu/delta ratio decrease for all TMP conformations, compared with the parent compound (DPDPE). Octanol/buffer distribution analysis showed enhanced lipophilicity of all TMP forms, with a sixfold enhancement associated with (2S,3S)-TMP. In situ vascular perfusion in anesthetized rats showed a 1.6-fold (p < 0.01) increase in the ratio of brain uptake for (2S,3S)-TMP and a 1.5-fold (p < 0.01) decrease in uptake for (2R,3R)-TMP. Saturability of (2S,3S)-TMP was shown (p < 0.01) against 100 microM unlabeled DPDPE, showing a shared nondiffusionary transport system. P-glycoprotein affinity was shown in situ for the parent and (2S,3S)-TMP (p < 0.01). Protein binding capacity of the TMP compounds in rat plasma and in situ mammalian bovine serum albumin-Ringer showed (2R,3S)-TMP and (2S,3R)-TMP with the lowest degree of protein binding (p < 0.01), and (2S,3S)-TMP and (2R,3R)-TMP with comparable affinities to DPDPE. Analgesia, via intravenous administration, showed significantly reduced (p < 0.01) end effect and time course for (2R,3R)-TMP, (2R,3S)-TMP, and (2S, 3R)-TMP as compared with DPDPE. These results demonstrate that topographical modification in a conformationally restricted peptide can significantly modulate potency and receptor selectivity, binding capacity, enzymatic stability, lipophilicity, P-glycoprotein affinity, and blood-brain barrier permeability, resulting in a change of bioavailability, and thereby provides insight for future peptide drug design.
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| pubmed:grant | |
| pubmed:language |
eng
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| pubmed:journal | |
| pubmed:citationSubset |
IM
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| pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/Alanine,
http://linkedlifedata.com/resource/pubmed/chemical/Enkephalin, D-Penicillamine (2,5)-,
http://linkedlifedata.com/resource/pubmed/chemical/P-Glycoprotein,
http://linkedlifedata.com/resource/pubmed/chemical/Receptors, Opioid, delta,
http://linkedlifedata.com/resource/pubmed/chemical/Receptors, Opioid, mu
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| pubmed:status |
MEDLINE
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| pubmed:month |
Jul
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| pubmed:issn |
0022-3042
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| pubmed:author | |
| pubmed:issnType |
Print
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| pubmed:volume |
75
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| pubmed:owner |
NLM
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| pubmed:authorsComplete |
Y
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| pubmed:pagination |
424-35
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| pubmed:dateRevised |
2007-11-14
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| pubmed:meshHeading |
pubmed-meshheading:10854288-Alanine,
pubmed-meshheading:10854288-Analgesia,
pubmed-meshheading:10854288-Animals,
pubmed-meshheading:10854288-Blood-Brain Barrier,
pubmed-meshheading:10854288-Brain,
pubmed-meshheading:10854288-Capillaries,
pubmed-meshheading:10854288-Cattle,
pubmed-meshheading:10854288-Endothelium, Vascular,
pubmed-meshheading:10854288-Enkephalin, D-Penicillamine (2,5)-,
pubmed-meshheading:10854288-Female,
pubmed-meshheading:10854288-Methylation,
pubmed-meshheading:10854288-Molecular Conformation,
pubmed-meshheading:10854288-P-Glycoprotein,
pubmed-meshheading:10854288-Rats,
pubmed-meshheading:10854288-Rats, Sprague-Dawley,
pubmed-meshheading:10854288-Receptors, Opioid, delta,
pubmed-meshheading:10854288-Receptors, Opioid, mu,
pubmed-meshheading:10854288-Stereoisomerism,
pubmed-meshheading:10854288-Structure-Activity Relationship
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| pubmed:year |
2000
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| pubmed:articleTitle |
Assessment of stereoselectivity of trimethylphenylalanine analogues of delta-opioid [D-Pen(2),D-Pen(5)]-enkephalin.
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| pubmed:affiliation |
Department of Pharmacology, University of Arizona, College of Medicine, Tucson, Arizona, USA.
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| pubmed:publicationType |
Journal Article,
Comparative Study,
Research Support, U.S. Gov't, P.H.S.
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