A Novel Peptide Cleavage Reaction

Mazur, Robert H.; Schlatter, James M.

doi:10.1021/jo01039a037

Cited by 44 publications

(17 citation statements)

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“…The normalization CN and the scaling factor (TN are explicitly written as (13) (TN 2 = (RN 2 )r e~1) / r e~3), (14) respectively, where r(z) denotes the gamma function of the argument z and (RN 2 ) the mean-square end-toend distance for N steps. The mean-square radius of gyration is given by…”

Section: Theoreticalmentioning

confidence: 99%

Rayleigh Scattering by Linear Flexible Macromolecules

Utiyama

Tsunashima

Kurata

1971

The Journal of Chemical Physics

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Precise light-scattering measurements were made on poly-a-methylstyrene samples with sharp molecular weight distribution, the molecular weight ranging from about 400 thousand to 7 million. The specific reduced scattered intensity at infinite dilution was determined for 18 scattering angles in the range of 9°-150°, in trans-decal in at 9.6° (theta temperature), 15.2, 29.4, 91.3°C, and in benzene at 30.0°C. In trans-decalin, the particle scattering factor P obtained is in good agreement with the well-known Debye equation irrespective of the temperature and the molecular weight. Experimental results in good solvent, benzene, are also well represented by the Debye equation for 1~P~O.15, but significant deviation is observed for PN(R)=CNRI exp[-(R/u)tJ, is used for polymer chains of N segments with excluded volume effects. CN is the normalizing constantj u is related to the standard deviation of Rj and 1=2/(1-.), where. is defined by (R2)=AN1+·. A is a numerical constant. The parameter I obtained by fitting the experimental data to the theory was found to increase with. and to be slightly greater than I.

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Section: Theoreticalmentioning

confidence: 99%

Rayleigh Scattering by Linear Flexible Macromolecules

Utiyama

Tsunashima

Kurata

1971

The Journal of Chemical Physics

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“…One potential liability with small peptides is the spontaneous formation of diketopiperazines during peptide synthesis (Marsden ef a/., 1993;Mazurov ef a/., 1993;Capasso ef a/., 1995), which appears to be catalyzed by phosphate (Takoakaef a/., 1991) and acidic conditions as evidenced by the formation of c(His-Pro) (Mazur and Schlatter, 1963), c[(2-methyl)Ala-Pro] (Gerig and McLeod, 1976) or c(His-Pip) and c(His-Pro) from tripeptide intermediates (Nutt ef a/., 1981). On the other hand, H-Dmt-Tic-OH (Salvador!…”

Section: Introductionmentioning

confidence: 99%

Opioid Diketopiperazines: Synthesis and Activity of a Prototypic Class of Opioid Antagonists

Balboni¹,

Guerrini²,

Salvadori³

et al. 1997

Biological Chemistry

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Discovery of high affinity and ultraselective delta opioid dipeptide antagonists composed of 2',6'-dimethyl-L-tyrosyl (Dmt) and 1,2,3,4-tetrahydroisoquinoline-3-carboxylic (Tic) served as the basis for the conformationally restricted diketopiperazine cyclo(Dmt-Tic) and related open chain analogues. These peptides primarily bind to delta opioid receptors: c(Dmt-Tic) displayed 30- to 50-fold higher delta affinity (Ki delta) than its diastereo-isomeric analogues and more than 4000-fold greater than its Tyr cognate; all of the c(Tyr-Tic) analogues were essentially inactive; c[(N-methyl)Dmt-Tic] lost 5-fold in Ki delta, while Ki mu increased 10-fold to yield a nonselective peptide; and the c(Dmt-Phe) series exhibited considerably reduced binding which indicated a synergism between Dmt and Tic in the binding mechanism. Whereas acetyl-Dmt-Tic linear peptides weakly interacted with opioid receptors, Ac-Dmt-Tic-NH2, exhibited better delta antagonist activity than c(Dmt-Tic) and greater delta receptor selectivity (Ki mu/Ki delta = 570). A three point attachment hypothesis for the interaction between c(Dmt-Tic) and the delta receptor was proposed: hydrophobicity imparted by the aromatic rings and the methyl groups of Dmt, hydrogen bonding through the tyramine hydroxyl group, and cation-pi interactions were suggested as contributing factors in binding the diketopiperazine in the receptor pocket. Although c(Dmt-Tic) exhibited a weak antagonist activity with mouse vas deferens, this diketopiperazine may provide a scaffolding for the formation of more potent antagonists for potential therapeutic applications.

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“…This reaction might decrease the activity ofligands. This phenomenon occurs not only for peptides containing Tic or other constrained residues at the C-terminus, but also with other amino acids (6). On the basis of these results we have synthetised N-alkylated analogue of Dmt-Tic with the purpose of avoiding the diketopiperazine formation (7).…”

Section: Introductionmentioning

confidence: 91%

Tritiation of delta opioid-receptor selective antagonist dipeptide ligands with extraordinary affinity containing 2′, 6′dimethyltyrosine

et al. 1999

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Recently a new class of ~ opioid antagonists has been discovered by using Tyr-Tic sequence. The substitution of Tyr 1 by Dmt resulted in a new analogue (H-Dmt-Tic-OH) with enhanced affinity and selectivity. Because of its excellent property we chose it for labelling with tritium. At the same time peptides containing Tic at position 2 undergo spontaneous diketopiperazine formation in some solvents, and they lose some of their binding ability. To avoid this unwanted side-reaction we synthetized the N-methylated analogue (N,N(Me)2-Dmt-Tic-OH), and it was more stable under storage condition, but 5 affinity declined moderately. On the basis of this information we prepared diiodinated analogues of these dipeptides. Catalytic dehalotritiation of precursors resulted in tritiated peptides. High specific radioactivity, 44.67 Ci/mmol with [3H]Dmt-Tic-OH and 59.88 Ci/mmol with N,N(Me)2-[ 3H]Dmt-Tic-OH were achieved. IntroductionThe heterogeneity ofopioid receptors is well established and it is accepted that there are at least three types of opioid receptor (~t, 5 and K). As no opioid ligand has been found to exhibit absolute specificity for any particular receptor type, several labzoratories have made an effort to develop ligands that have as high specificity as possible. Recently opioid dipeptide antagonists containing tyrosine and 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (Tic) (1) have been described for the 5 receptor. Replacement of Tyr by the more hydrophobic residue 2',6'-dimethyltyrosine (Dmt) resulted in new analogues. The peptide Dmt-Tic retained in vitro 5 opioid antagonism (2) and exhibit exceptional 5 receptor affinity (Ki5 = 0.022 nM) and extraordinary high selectivity (Ki~/Ki5 = 150000). One liability of small peptides is cyclization to a diketopiperazine during storage in acidic or some inorganic media (3,4,5). This reaction might decrease the activity ofligands. This phenomenon occurs not only for peptides containing Tic or other constrained residues at the C-terminus, but also with other amino acids (6). On the basis of these results we have synthetised N-alkylated analogue of Dmt-Tic with the purpose of avoiding the diketopiperazine formation (7). N,N-Dimethylation affected the 5 receptor binding properties and the affinity of N,N(Me)2-Dmt-Tic-OH moderately declined (5-fold) in comparison with that of H-Dmt-Tic-OH; however a 5 affinity (Ki5 = 0.118 nM) and selectivity of 20000 took it an exceptional opioid ligand.

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A Novel Peptide Cleavage Reaction

Cited by 44 publications

References 0 publications

Rayleigh Scattering by Linear Flexible Macromolecules

Rayleigh Scattering by Linear Flexible Macromolecules

Opioid Diketopiperazines: Synthesis and Activity of a Prototypic Class of Opioid Antagonists

Tritiation of delta opioid-receptor selective antagonist dipeptide ligands with extraordinary affinity containing 2′, 6′dimethyltyrosine

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