ISSN:
1471-4159
Source:
Blackwell Publishing Journal Backfiles 1879-2005
Topics:
Medicine
Notes:
Abstract : [D-Pen2,D-Pen5]-Enkephalin (DPDPE) is an enzymatically stable δ-opioid receptor-selective peptide, which was modified by the trimethylation of the Phe4 residue to give β-methyl-2′,6′-dimethylphenylalanine (TMP), resulting in four conformations : (2R,3S)-β-Phe-DPDPE, (2R,3R)-β-Phe-DPDPE, (2R,3S)-β-Phe-DPDPE, and (2S,3R)-β-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 (δ- versus μ-opioid receptor) were evaluated by radioreceptor binding in rat brain, with a μ/δ 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 μM 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.
Type of Medium:
Electronic Resource
URL:
http://dx.doi.org/10.1046/j.1471-4159.2000.0750424.x
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