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1.
SEVERO SALVADORI REMO GUERRINI PIERO ANDREA BOREA ROBERTO TOMATIS 《Chemical biology & drug design》1992,40(5):437-444
The synthesis of pseudotetrapeptides H-Tyr-D-Ala-Phe-NH-(CH2)2-NH2 (1a), H-Tyr-D-Ala-Phe-ψ(CH2-NH)-Gly-NH2 (2a), H-Tyr-D-Ala-ψ(CH2-NH)-Phe-Gly-NH2 (3a), and H-Tyr-ψ(CH2-NH)-D-Ala-Phe-Gly-NH2 (4a), representing the N-terminal tetrapeptide sequence of dermorphin, in which amide bonds are replaced by CH2-NH bond, is described. N-acetyl-Tyr and desamino-Tyr pseudopeptide analogs (1-4b), (1-3c) are also described. The analogs were assayed in binding studies based on displacement of μ and δ-receptor selective radiolabels from rat brain membrane and in a bioassay using guinea pig ileum (GPI). Pseudopeptides in which the C-terminal (1a) or D-Ala-Phe (3a) amide bond are substituted, exhibit higher μ-affinities and μ-receptor selectivity than the corresponding Phe-Gly or Tyr-D-Ala analogs (2a, 4a). Acetyl-and desamino-Tyr pseudopeptide analogs (1-4b) and (1-3c) did not exhibit μ and δ-opioid receptor affinity at nM concentration. The relevance of the single peptide replacement and of its association to acetylation or amino group elimination of Tyr, is discussed on the basis of a receptor model for μ and δ opioids. 相似文献
2.
The previously described cyclic delta opioid receptor-selective tetrapeptide H-Tyr-d -Cys-Phe-d -Pen-OH (JOM-13) was modified at residue 3 by incorporation of both natural and unnatural amino acids with varying steric, electronic, and lipophilic properties. Effects on mu and delta opioid receptor binding affinities were evaluated by testing the compounds for displacement of radiolabeled receptor-selective ligands in a guinea pig brain receptor binding assay. Results obtained with the bulky aromatic 1-Nal3 and 2-Nal3 substitutions suggest that the shape of the receptor subsite with which the side chain of the internal aromatic residue interacts differs for delta and mu receptors. This subsite of either receptor can accommodate the transverse steric bulk of the 1-Nal3 side chain but only the delta receptor can readily accept the more elongated 2-Nal3 side chain. Several analogs with pi-excessive heteroaromatic side chains in residue 3 were examined. In general, these analogs display diminished binding to mu and delta receptors, consistent with previous findings for analogs with residue 3 substitutions of modified electronic character. Several analogs with alkyl side chains in residue 3 were also examined. While delta receptor binding affinity is severely diminished with Val3, Ile3, and Leu3 substitutions, Cha3 substitution is very well tolerated, indicating that, contrary to the widely held belief, an aromatic side chain in this portion of the ligand is not required for delta receptor binding. Where possible, comparison of results in this delta-selective tetrapeptide series with those reported for analogous modification in the cyclic delta-selective pentapeptide [d -Pen2, d -Pen5]enkephalin (DPDPE) and linear pentapeptide enkephalins reveals similar trends. 相似文献
3.
Synthesis by a classical solution method of a sulphated analogue of dermorphin is reported. The product has proved to be devoid of any peripheral and central opiate- or CCK-like activity in the tests assayed. 相似文献
4.
SEVERO SALVADORI MAURO MARASTONI GIANFRANCO BALBONI GIULIANO MARZOLA ROBERTO TOMATIS 《Chemical biology & drug design》1986,28(3):254-261
Dehydrophenylalanine having the Z-configuration (ΔPhe) and D-Phe were incorporated in positions 3 and/or 5 into dermorphin-(1–5)-peptide amide (H-Tyr-D-Ala-Phe-Gly-Tyr-NH2) in order to study the effect of structure or configurational changes. On GPI preparation, whereas the activity of [L-Phe5]-pentapeptide was fourfold higher than parent peptide and comparable to that of dermorphin, the substitution of Phe3 by its D-enantiomer was barely tolerated. The pentapeptides containing ΔPhe in positions 3 and/or 5 displayed even lower potency: particularly the unsaturation at position 3 alone or at position 3 and 5 was very detrimental to μ activity. 相似文献
5.
SEVERO SALVADORI MAURO MARASTONI GIANFRANCO BALBONI PIERANDREA BOREA ROBERTO TOMATIS 《Chemical biology & drug design》1989,33(2):94-102
C-Terminal amino acid residues of dermorphin (H-Tyr-D-Ala-Phe-Gly-Tyr-Pro-Ser-NH2) were replaced by Nα-methyl- or D-amino acids in order to examine the effect on opioid activity. In binding studies based on displacement of μ, Δ, and κ opioid receptor selective radiolabels from guinea pig brain membranes, the 13 new analogues showed, like dermorphin, a negligible affinity for the κ binding site. The introduction of Nα-methyl- or D-amino acid residues at position 5, 6, or 7 of dermorphin, when matched with C-terminal amide function modifications, generally produced analogues with reversed μ/δ specificity. 相似文献
6.
MAURO MARASTONI SEVERO SALVADORI GIANFRANCO BALBONI GIULIANO MARZOLA ETTORE CIRO DEGLIUBERTI ROBERTO TOMATIS 《Chemical biology & drug design》1986,28(3):274-281
Dermorphinoyl(DMR)-glycine, DMR-sarcosine and DMR-glycyl-arginine have been prepared in order to examine the effect of C-terminal extension of dermorphin (H-Tyr-D-Ala-Phe-Gly-Tyr-Pro-Ser-NH2) on opioid activity. On GPI preparation the addition of Gly, Sar, or Gly-Arg to the carboxyl terminus of dermorphinoic acid was detrimental to μ activity: dermorphinoyl-derivatives, in fact, retain only 5–20% of dermorphin potency. Following intracerebroventricular administration (tail-flick test), whereas the analgesic activities of compounds showed the trend dermorphin >DMR-Sar> DMR-Gly-Arg>DMR-Gly>morphine, the nonapeptide displayed highest activity after subcutaneous injection in mice: DMR-Gly-Arg was 2.5 and 10 times more potent than dermorphin and morphine, respectively. 相似文献
7.
O. V. Eshchenko K. A. Nikol'skaya V. I. Deigin E. P. Yarova 《Bulletin of experimental biology and medicine》1998,126(3):866-868
The effect of a dermorphin analog on learning was studied in a Wistar rat model of the complex food-seeking task. The preparation
decreased the degree of anxiety in a dose-independent manner. In a dose of 50 μg/kg it increased the number of “well”-learning
rats by intensifying the learning process in rats with initially suppressed cognitive activity. In a dose of 150 μg/kg, the
opioid decreased the number of “well”-learning rats due to disturbance of motivation mechanisms, which was manifested in behavioral
instability.
Translated fromByulleten' Eksperimental'noi Biologii i Meditsiny, Vol. 126, No. 9, pp. 252–255, September, 1998 相似文献
8.
E. Yu. Baturina N. Yu. Sarycheva V. I. Deigin E. P. Yarova A. A. Kamenskii I. P. Ashmarin 《Bulletin of experimental biology and medicine》1988,105(2):202-204
Laboratory Complex, M. V. Lomonosov Moscow University. Translated from Byulleten' Éksperimental'noi Biologii i Meditsiny, Vol. 105, No. 2, pp. 177–179, February, 1988. 相似文献
9.
Abstract: In order to extend the use of proteases to organic synthesis and seek the rules of enzymatic reactions in organic media, we focused on unnatural substrates for proteases to form amide bonds. In this paper, the study of unnatural substrates containing d ‐amino acid residue, which act as acyl acceptors as well as acyl donors for proteases in organic media, is reported. Dermorphin is a heptapeptide (H‐Tyr‐d ‐Ala‐Phe‐Gly‐Tyr‐Pro‐Ser‐NH2) with potent analgesic activity. The N‐terminal tetrapeptide is the minimum sequence that retains dermorphin activity, and is selected as the model compound in our study. Two dermorphin‐(1–4) derivatives, Boc‐Tyr‐d ‐Ala‐Phe‐Gly‐N2H2Ph and Boc‐Tyr‐d ‐Ala‐Phe‐Gly‐NH2, which contained a d ‐amino acid residue, were synthesized by proteases in organic media for the first time. The synthesis of these two dermorphin‐(1–4) derivatives could be catalyzed by subtilisin with Boc‐Tyr‐d ‐Ala‐OCH2CF3 as an acyl donor substrate in AcOEt. The synthesis of dermorphin‐(1–2) derivative Boc‐Tyr‐d ‐Ala‐N2H2Ph was catalyzed by α‐chymotrypsin in different organic solvents and d ‐Ala‐N2H2Ph was used as an acyl acceptor substrate. Factors influencing the above enzymatic reactions were systematically studied. 相似文献
10.
Abstract: Dermorphin and [Lys7]dermorphin, selective µ‐opioid receptor ligands originating from amphibian skin, have been modified with various electrophiles in either the ‘message’ or ‘address’ sequences as potential peptide‐based affinity labels for µ‐receptors. Introduction of the electrophilic isothiocyanate and bromoacetamide groups on the para position of Phe3 and Phe5 was accomplished by incorporating Fmoc‐Phe(p‐NHAlloc) into the peptide followed by selective deprotection and modification. The corresponding amine‐containing peptides were also prepared. The pure peptides were evaluated in radioligand binding experiments using Chinese hamster ovary (CHO) cells expressing µ‐ and δ‐opioid receptors. In dermorphin, introduction of the electrophilic groups in the ‘message’ domain lowered the binding affinity by > 1000‐fold; only [Phe(p‐NH2)3]dermorphin retained nanomolar affinity for µ‐receptors. Modifications in the ‘address’ region of both dermorphin and [Lys7]dermorphin were relatively well tolerated. In particular, [Phe(p‐NH2)5,Lys7]dermorphin showed similar affinity to dermorphin, with almost 2‐fold higher selectivity for µ‐receptors. [Phe(p‐NHCOCH2Br)5]‐ and [Phe(p‐NHCOCH2Br)5,Lys7]dermorphin exhibited relatively high affinity (IC50 = 27.7 and 15.1 nm , respectively) for µ‐receptors. However, neither of these peptides inhibited [3H]DAMGO binding in a wash‐resistant manner. 相似文献