Opioid analogues studies

The three prototype mixed p agonist/S antagonists described in this chapter have excellent potential as analgesics with low propensity to produce tolerance and dependence. The pseudotetrapeptide DIPP-NH2[ ] has already been shown to produce a potent analgesic effect, less tolerance than morphine, and no physical dependence upon chronic administration. In preliminary experiments, the tetrapeptides DIPP-NH2 and DIPP-NH2[T] were shown to cross the BBB to some extent, but further structural modifications need to be performed in order to improve the BBB penetration of these compounds. The Tyr-Tic dipeptide derivatives can also be expected to penetrate into the central nervous system because they are relatively small, lipophilic molecules. In this context, it is of interest to point out that the structurally related dipeptide H-Dmt-D-Ala-NH-(CH2)3-Ph (SC-39566), a plain p-opioid agonist, produced antinociception in the rat by subcutaneous and oral administration [72], As indicated by the results of the NMR and molecular mechanics studies, the conformation of the cyclic p-casomorphin analogue H-Tyr-c[-D-Orn-2-Nal-D-Pro-Gly-] is stabilized by intramolecular hydrogen bonds. There-... 

Initial studies of brain delivery based on the chimeric peptide strategy used the absorptive-mediated uptake of cationized albumin which was chemically coupled to the opioid peptide P-endorphin [80] or its metabohcaUy stabilized analogue [D-Ala ]P-endorphin. Tracer experiments in which the chimeric peptide was labelled in the endorphin moiety provided evidence of internalization by isolated brain capillaries and transport into brain tissue in vivo [81]. 

The geometric isomers 464 and 467 of 5(47/)-oxazolones prepared from acetophenones can be separated. Alternatively, the mixture can be isomerized under the appropriate reaction conditions to obtain the pure of (Z) or ) isomer. Each isomer can be converted to a pair of enantiomers 466 and 469 (only one enantiomer shown) (Scheme 7.152). The p-methyl phenylalanine analogues thus obtained are constrained phenylalanines and the effect of incorporation of a p-MePhe or p-MeTyr residue on the biological properties of H-Tyr-Tic-Phe-Phe-NH2 (TIPP, where Tic = l,2,3,4-tetrahydroisoquinoline-3-carboxylic acid) a delta opioid receptor antagonist, has been studied. ... 

Peptide cyclization significantly reduces this flexibility, as shown by model studies with cyclic pseudodipeptides. When incorporated into biologically active cyclic peptides, potencies are generally retained or even enhanced. But flexibility is still a feature since pseudopeptide analogues of the p-receptor-selective opioid parent peptide, Tyr-c[-D-Lys-Gly-Phe-Leu-], were potent but nonselective with respect to activity toward p- and 6-re-ceptorsJ50]... 

An interesting comparison can be made looking at the a- and (5-tetralin derivatives entries—15/16 and —17 in Table 1 which can be regarded as cyclic confor-mationally constrained analogues of phenylglycine and phenylalanine. In an interesting study, 6-hydroxy-2-aminotetralin-2-carboxylic acid 12 (Hat) has been incorporated as a conformationally constrained tyrosine analogue into S-opioid receptor selective tetrapeptides.114 15 Whereas entry 15, the (S)-a-tetralin deriva-... 

The results of structure-activity studies on opioid peptides revealed that analogues consisting entirely of aromatic amino acids, such as H-Tyr-D-Phe-Phe-NH2 [26] and H-Tyr-D-Phe-Phe-Phe-NH2 [27] were quite potent and selective q-agonists. Systematic replacement of the amino acids in these two peptides... 

Morphine The Prototype Opioid Ligand 262 11.4.1 Initial Studies of Morphine Analogues 263... 

In a double-blind, placebo-controUed study in 24 elderly patients scheduled for elective total hip replacement who were randomized to either intrathecal morphine 160 pg or nalbuphine 400 pg postoperatively, when the pain score was greater than 3 cm on a visual analogue scale, nalbuphine produced significantly faster onset and shorter duration of analgesia (5). Both opioids produced adequate maximal pain rehef in aU patients. The adverse effects profile was umemarkable in both groups. 

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