263239-05-0Relevant articles and documents
Stereospecific synthesis of (2S)-2-methyl-3-(2′,6′-dimethyl-4′-hydroxyphenyl)-propionic acid (Mdp) and its incorporation into an opioid peptide
Lu, Yixin,Weltrowska, Grazyna,Lemieux, Carole,Chung, Nga N.,Schiller, Peter W.
, p. 323 - 325 (2007/10/03)
To examine the effect of replacing the N-terminal amino group in opioid peptides with a methyl group on biological activity, a stereospecific synthesis of the tyrosine analogue (2S)-2-methyl-3-(2′,6′-dimethyl-4′-hydroxyphenyl)-propionic acid (Mdp) was performed. The enkephalin analogue (2S)-Mdp-D-Ala-Gly-Phe-Leu-NH2 turned out to be a quite potent δ opioid antagonist and a somewhat less potent μ antagonist, indicating that a positively charged N-terminal amino group is not a conditio sine qua non for the binding of opioid peptides to δ and μ receptors but may be required for signal transduction.
Stereospecific syntheses of 2-alkyl and 2-phenyl substituted 3-(2,6-dimethyl-4-hydroxyphenyl)propanoic acids
Lu,Schiller
, p. 1639 - 1644 (2007/10/03)
Stereospecific syntheses of 2-methyl-, 2-ethyl-, 2-cyclohexyland 2-phenyl- substituted 3-(2,6-dimethyl-4-hydroxyphenyl)propanoic acids were developed. The key steps for the formation of the stereogenic centers involved the utilization of Evans' 4-benzyl-2-oxazolidinone chiral auxiliary. These compounds were designed to replace the N-terminal tyrosine residue in opioid peptides.
Novel ligands lacking a positive charge for the δ- and μ-opioid receptors
Schiller, Peter W.,Berezowska, Irena,Nguyen, Thi M.-D.,Schmidt, Ralf,Lemieux, Carole,Chung, Nga N.,Falcone-Hindley, Margaret L.,Yao, Wenqing,Liu, Josephine,Iwama, Seiji,Smith III, Amos B.,Hirschmann, Ralph F.
, p. 551 - 559 (2007/10/03)
Recently we reported using minilibraries to replace Lys [somatostatin (SRIF) numbering] of the potent somatostatin agonist L-363,301 (c[-Pro-Phe-D- Trp-Lys-Thr-Phe-]) to generate the potent neurokinin receptor (NK-1) antagonist c[-Pro-Phe-D-Trp-p-F-Phe-Thr-Phe-]. This novel cyclic hexapeptide did not bind the SRIF receptor. Thus, a single mutation converted L-363,-301, a SRIF agonist with potency ca. 2-8 times the potency of SRIF in laboratory animals, into a selective NK-1 receptor antagonist with an IC50 of 2 nM in vitro. During the screening of the same libraries for ligands of the δ- opioid receptor, we identified four compounds (1-4) which represent a new class of δ-opioid antagonists, some of which were also NK-1 receptor antagonists. The most potent δ-opioid antagonist, c[-Pro-1-Nal-D-Trp-Tyr- Thr-Phe-] (2), showed a K(e) value of 128 nM in the mouse vas deferens assay and a δ-receptor binding affinity constant of 152 nM in the rat brain membrane binding assay. These results are of interest because they represent a novel class of δ-opioid antagonists and, like two previously reported δ- opioid antagonists, they lack a positive charge. To examine further the requirement for a positive charge in the δ-opioid ligands, we prepared two analogues of the β-casomorphin-derived mixed μ-agonist/δ-antagonist, H- Dmt-c[-D-Orn-2-Nal-D-Pro-Gly-] (7), in which we eliminated the positive charge either through formylation of the primary amino group (5) or by the deletion of this N-terminal amino group (6). These latter compounds proved to be δ-opioid antagonists with K(e) values in the 16-120 nM range, as well as fairly potent μ-opioid antagonists (K(e) ? 200 nM). These six compounds provide the most convincing evidence to date that there is no requirement for a positive charge in μ- and δ-opioid receptor antagonists. In addition, cyclic, hexapeptide 4 lacks a phenolic hydroxyl group. Taken together, these data suggest that the prevailing assumptions about δ- and μ-opioid receptor binding need revision and that the receptors for these opioid ligands have much in common with the NK-1 and somatostatin receptors.
