Synthesis and Pharmacological Evaluation of Highly Potent [Dmt1]DALDA Analogs (original) (raw)
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[Dmt1]DALDA analogues modified with tyrosine analogues at position 1
Bioorganic & Medicinal Chemistry Letters, 2016
Analogues of [Dmt 1 ]DALDA (H-Dmt-D-Arg-Phe-Lys-NH 2 ; Dmt = 2′,6′-dimethyltyrosine), a potent μ opioid agonist peptide with mitochondria-targeted antioxidant activity were prepared by replacing Dmt with various 2′,6′-dialkylated Tyr analogues, including 2′,4′,6′-trimethyltyrosine (Tmt), 2′-ethyl-6′-methyltyrosine (Emt), 2′-isopropyl-6′-methyltyrosine (Imt) and 2′,6′diethyltyrosine (Det). All compounds were selective μ opioid agonists and the Tmt 1-, Emt 1 and Det 1-analogues showed subnanomolar μ opioid receptor binding affinities. The Tmt 1-and Emt 1analogues showed improved antioxidant activity compared to the Dmt 1-parent peptide in the DPPH radical-scavenging capacity assay, and thus are of interest as drug candidates for neuropathic pain treatment.
DALDA analogues containing alpha-hydroxymethylamino acids
Acta biochimica Polonica, 2001
To evaluate the role of aromatic amino-acids residues, four analogues of the mu-selective opioid peptide agonist DALDA (H-Tyr-D-Arg-Phe-Lys-NH2) containing the amphiphilic, a,a-disubstituted amino acid (R)- or (S)-alpha-hydroxymethyltyrosine (HmTyr) in position 1 and (R)- or (S)-alpha-hydroxymethylphenylalanine (HmPhe) in position 3 of the peptide sequence were synthesized. Only the [(R)-HmPhe3)]DALDA analogue displayed full agonistic activity in both the guinea pig ileum and the mouse vas deferens assays and turned out to be a delta receptor-selective opioid agonist.
Synthesis of Tetrapeptides and Screening of their Antioxidant Properties
Current Bioactive Compounds
Background: Tetrapeptide Pro-Ala-Gly-Tyr (PAGY) is an antioxidant peptide that was isolated by Nikoo et al. (2014) from hydrolysate of skin gelatin of amur sturgeon fish (Acipenser schrenckii). This research aims to synthesize PAGY and its analogues by a solid-phase method, and to screen their antioxidant activities. Methods: PAGY and its analogues, namely, Pro-Ser-Gly-Tyr (PSGY), Pro-Ala-Phe-Tyr (PAFY), Pro- Phe-Phe-Tyr (PFFY) and Pro-Ala-Ile-Tyr (PAIY), were synthesized via a solid phase peptide synthesis method with the Fmoc/t-Bu strategy. The synthesis was undertaken on 2-chlorotritylchloride resin as solid support, and all coupling reactions were facilitated by a combination of HBTU and HOBt reagents. All peptides were cleaved from the resin by using 95% TFA in water. Results: Through the solid-phase synthesis method, all peptides were obtained in 50-85% yields. Pure peptides were analysed by analytical RP-HPLC, and were characterized by HR-TOF-ESI-MS and 1HNMR. DPPH inhibition...
ELECTROPHORESIS, 2006
In the present study, we have monitored the oxidation process of novel nontoxic neuropeptides and determined its rate constants, which describe the antioxidative potential of the peptides. A capillary electrophoretic method was implemented which ensures the simultaneity of analysis of reactants and products in a short time of analysis. The rate constants of oxidation of the four novel peptides, 4-methoxy-L-tyrosinylg-L-glutamyl-L-cysteinyl-glycine (UPF1), D-serinyl-g-L-glutamyl-L-cysteinyl-glycine (UPF6), 4-methoxy-L-tyrosinyl-a-L-glutamyl-L-cysteinyl-glycine and D-serinyl-a-L-glutamyl-L-cysteinyl-glycine, designed by us, were compared with those of oxidation of glutathione (reduced glutathione) by using capillary electrophoresis. The second-order rate constants were similar for all peptides if the oxidation was carried out with hydrogen peroxide (k II = 0.208 2 0.236610 3 /M?min). The rate constants were also determined for the mixtures of peptides. When the oxidation is caused by hydroxyl radical (OH*), the g-glutamate containing peptides (UPF1 and UPF6) exhibited two to four times higher antioxidative activity (k II = 4.428 and 2.152610 3 /M?min, respectively). The results suggest that the antioxidative potential of the peptides studied is not determined by the formation of disulphide bridge alone.
Synthesis and Biological Evaluation of d Amino Acid Oxidase Inhibitors
Journal of Medicinal Chemistry, 2008
D-Amino acid oxidase (DAAO) catalyzes the oxidation of D-amino acids including D-serine, a full agonist at the glycine site of the NMDA receptor. A series of benzo[d]isoxazol-3-ol derivatives were synthesized and evaluated as DAAO inhibitors. Among them, 5-chlorobenzo[d]isoxazol-3-ol (CBIO) potently inhibited DAAO with an IC50 in the submicromolar range. Oral administration of CBIO in conjunction with D-serine enhanced the plasma and brain levels of D-serine in rats compared to the oral administration of D-serine alone.
Helvetica Chimica Acta, 1998
We report on the synthesis of new and previously described b-peptides (1 ± 6), consisting of up to twelve b 2,2 -or b 3,3 -geminally disubstituted b-amino acids which do not fit into any of the secondary structural patterns of b-peptides, hitherto disclosed. The required 2,2-and 3,3-dimethyl derivatives of 3-aminopropanoic acid are readily obtained from 3-methylbut-2-enoic acid and ammonia (Scheme 1) and from Boc-protected methyl 3aminopropanoate by enolate methylation (Scheme 2). Protected (Boc for solution-, Fmoc for solid-phase syntheses) 1-(aminomethyl)cycloalkanecarboxylic-acid derivatives (with cyclopropane, cyclobutane, cyclopentane, and cyclohexane rings) are obtained from 1-cyanocycloalkanecarboxylates and the corresponding dihaloalkanes (Scheme 3). Fully 13 C-and 15 N-labeled 3-amino-2,2-dimethylpropanoic-acid derivatives were prepared from the corresponding labeled precursors (see asterixed formula numbers and Scheme 4). Coupling of these amino acids was achieved by methods which we had previously employed for other b-peptide syntheses (intermediates 18 ± 23). Crystal structures of Boc-protected geminally disubstituted amino acids (16a ± d) and of the corresponding tripeptide (23a), as well as NMR and IR spectra of an isotopically labeled b-hexapeptide (2a*) are presented (Figs. 1 ± 4) and discussed. The tripeptide structure contains a ten-membered H-bonded ring which is proposed to be a turn-forming motif for b-peptides .
Cyclic dermorphin tetrapeptide analogues obtained via ring-closing metathesis
2000
The dermorphin-derived cyclic tetrapeptide analogues H-Tyr-c[d-Cys-Phe-Cys]NH 2 and H-Tyrc[d-Cys-Phe-D-Cys]NH 2 are opioid agonists at the µ and δ receptor. To enhance the metabolic stability of these peptides, we replaced the disulfide bridge with a bis-methylene moiety. This was achieved by solid-phase synthesis of the linear precursor peptide containing allylglycine residues in place of the Cys residues, followed by ring-closing metathesis. In the case of the peptide with l-configuration in the 4-position both the cis and the trans isomer of the resulting olefinic peptides were formed, whereas the cis isomer only was obtained with the peptide having the d-configuration in position 4. Catalytic hydrogenation yielded the saturated-CH 2-CH 2-bridged peptides. In comparison with the cystine-containing parent peptides, all olefinic peptides showed significantly reduced µ and δ agonist potencies in the guinea pig ileum and mouse vas deferens assays. The-CH 2-CH 2-bridged peptide with l-configuration in the 4-position was equipotent with its cystine-containing parent in both assays, whereas the bis-methylene analogue with d-configuration in position 4 was 10-27-fold less potent compared to its parent. The effect of the disulfide replacements with the-CH=CH-and-CH 2-CH 2-moieties on the conformational behavior of these peptides was examined by theoretical conformational analysis which provided plausible explanations in terms of structural parameters for the observed changes in opioid activity.
Synthetic approaches to peptides containing the l-Gln-l-Val-D(S)-Dmt motif
Bioorganic & Medicinal Chemistry, 2007
The pseudoprolines S-Dmo (5,5-dimethyl-4-oxaproline) and R-Dmt (5,5-dimethyl-4-thiaproline) have been used to study the effects of forcing a fully cis conformation in peptides. Synthesis of peptides containing these (which have the same configuration as L L-Pro) is straightforward. However, synthesis of peptides containing S-Dmt is difficult, owing to the rapid cyclisation of L L-Aaa-S-Dmt amides and esters to form the corresponding diketopiperazines (DKP); thus the intermediacy of L L-Aaa-S-Dmt amides and esters must be avoided in the synthetic sequence. Peptides containing the L L-Gln-L L-Val-D(S)-Dmt motif are particularly difficult, owing to the insolubility of coupling partners containing Gln. Introduction of Gln as N-Boc-pyroglutamate overcame the latter difficulty and the dipeptide active ester BocPygValOC 6 F 5 coupled in good yield with S-DmtOH. BocPygVal-S-DmtNH(CH 2 ) 2 C 6 H 4 NO 2 was converted quantitatively to BocGlnVal-S-DmtNH(CH 2 ) 2 C 6 H 4 NO 2 with ammonia, demonstrating the utility of this approach. Two peptide derivatives (CbzSerLysLeuGlnVal-S-DmtNH(CH 2 ) 2 C 6 H 4 NO 2 and CbzSerSerLysLeuGln-Val-S-DmtNH(CH 2 ) 2 C 6 H 4 NO 2 ) were assembled, using these new methods of coupling a dipeptide acid active ester with S-DmtOH and introduction of Gln as Pyg, followed by conventional peptide couplings. The presence of the Val caused these peptides to be cleaved very slowly by prostate-specific antigen (PSA) at Leu # Gln, rather than the expected Gln # Val.