Tetrapeptide analogues

A number of tetrapeptide analogues related to morphiceptin were synthetized in which the proline in the second position was replaced with cis- or trans-2-ACPC [41, 169, 170]. The synthetic scheme is shown in Figure 1. The diastereomers were separated by using preparative HPLC. By means of this pathway, the following peptides were prepared Tyr-(lR,2iS)-ACPC-Phe-Val-NH2, Tyr-(lS,2R)-ACPC-Phe-Val-NH2, Tyr-(l/ ,2iS)-ACPC-Phe-D-Val-NH2, Tyr-(lS,2R)-ACPC-Phe-D-Val-NH2, Tyr-( 1 R,25)-ACPC-Phe-Pro-NH2, Tyr-(lS,2R)-ACPC-Phe-Pro-NH2 and... 

Figure 4.11 Examples of Nishino and Yoshida s S5mthetic cyclic tetrapeptide analogues.

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-... 

Findings continue to accumulate in the field of endogenous opiates, as exemplified by two tetrapeptides isolated from mammalian brain and found to have high affinity and selectivity for p-opioid receptors. These tetrapeptides are endomorphin-1 (Tyr-Pro-Trp-Phe-NH2) and endomorphin-2 (Tyr-Pro-Phe-Phe-NH2). A number of synthetic analogues have been prepared with the view to improve their metabolic stability and, in some cases, to limit their access to peripheral opioid receptors. The three synthetic endomor-phin analogues Tyr-D-Ala-Phe-Phe-NH2 (6.84), Tyr-D-Arg-Phe-Phe-NH2 (6.85), and Tyr-D-Arg-Phe-Ape-NH2 (6.86), to be discussed in the next section, have potent antinociceptive effects in in vivo inflammatory tests but exhibit modest effects in the CNS. However, and despite the presence of a D-amino acid and a protected C-terminus, they remained sensitive to enzymatic hydrolysis [211][212],... 

K. Gademann, M. Ernst, D. Hoyer, D. Seebach, Synthesis and Biological Evaluation of a cyclo-/3-Tetrapeptide as a Somatostatin Analogue , Angew. Chem., Int. Ed. 1999, 38, 1223-1226. 

The hydroxamate functionality is an effective scissile bond surrogate in collagenase inhibitors [1,186-203], probably because of its ability to serve as a bidentate ligand for the active site Zn(II). N-terminal tri- and tetrapeptide hydroxamate substrate analogues are only moderately potent inhibitors Table 8.15). An intriguing observation with respect to possible binding modes is that the residues in subsites P and P2 can be replaced with their D-stereoisomer counterparts with essentially no loss of potency, as long as both are replaced with the D-isomers (compare (151), (152) and (153), and (154) vs. (157), in Table 8.15). 

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 N-terminal tetrapeptides of D-Met-deltorphin and D-Ala-deltor-phins did not show preference for delta receptors over mu receptors. The common determinants concurring to the remarkably efficient targeting of deltorphins towards the delta receptors were identified through structure-activity relationship studies conducted on an extensive series of synthetic analogues. The following structural requirements explain why the deltorphins are such potent and selective delta agonists a phenolic side chain (Tyr) and a... 

The first synthesis reported by Merrifield produced the desired tetrapeptide (Leu-Ala-Gly-Val).f l Amino acids, dipeptides, and tripeptides were all detected in the crude product released from the resin. Through continued improvements of the method, the high speed of the amino acid incorporation and automation, the solid-phase peptide synthetic methodology has become the method of choice for most laboratories synthesizing peptides. Shortly after the introduction of the solid-phase procedure it was used to synthesize insulin. This impressive achievement awakened the biochemical community to the promise of synthetic chemistry and initiated a period in which large numbers of peptide analogues were prepared and analyzed. 

Preparations of some A-substituted 2-oxo-l, 2-dihydropyrazines have been discussed in Section 11.2 from the reactions of di-, tri-, and tetrapeptides with glyoxal (380-382) and Cheeseman and co-workers (1111) have described the preparation of 1-benzyl-3-hydroxy-2-oxo-l, 2-dihydropyrazine (83) (and similarly its 1-methyl analogue) from ethyl A-(2, 2 -dimethoxyethyl)oxamate and benzyl-amine through A-benzyl-A -(2, 2-dimethoxyethyl)oxamide (84) by the application of a standard procedure (482). 

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