The Use of Conformational Restriction and Molecular Modeling Techniques in the Development of Receptor-Specific Opioid Peptide Agonists and Antagonists

Schiller, Peter W.; Nguyen, Tin; Weltrowska, Grazyna; Chung, Nga N.; Lemieux, Carole; Marsden, Brian J.; Wilkes, Brian C.

doi:10.1037/e495942006-018

Cited by 4 publications

(7 citation statements)

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“…On the other hand, the C‐terminus of the δ‐ligands (which tend to be free acids) occupies a region slightly lower in the putative receptor pocket. Schiller et al have demonstrated that the δ‐selectivity of TIPP‐NH 2 can be increased dramatically if the C‐terminal amide is replaced by the free acid [18]. Our model places the free acid in the location occupied by the free acid for the δ‐selective ligand DPDPE.…”

Section: Discussionmentioning

confidence: 95%

“…TIPP‐NH 2 on the other hand possessed a low energy conformation which is capable of filling both the μ‐selectivity pocket, as well as the δ‐selectivity region. Interestingly, TIPP‐NH 2 exhibits a dual μ‐agonist/δ‐antagonist profile [18].…”

Section: Discussionmentioning

confidence: 99%

“…We have studied the properties of endomorphin‐1 using NMR spectroscopy and molecular simulations, and the results have been complemented with molecular comparisons of this peptide with d ‐TIPP and PL‐017. Structural comparisons with the δ‐agonist DPDPE [11]and the dual μ‐agonist/δ‐antagonist, TIPP‐NH 2 [18]have also been performed to rationalize structure‐based selectivities among these ligands and opioid receptor types.…”

Section: Introductionmentioning

confidence: 99%

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Conformational analysis of the endogenous μ‐opioid agonist endomorphin‐1 using NMR spectroscopy and molecular modeling

Podlogar¹,

et al. 1998

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Endomorphin-1 (Tyr-Pro-Trp-Phe-NH P ) is a highly selective and potent agonist of the W W-opioid receptor. To identify structural attributes unique to this opioid peptide and potential sites of recognition, a conformational analysis has been performed using multidimensional NMR and molecular modeling techniques. The spectroscopic results, derived from experiments in both DMSO and water, indicate that endomorphin-1 exists in the cis-and trans-configuration with respect to the Pro-omega bond in approximately 25% and 75% populations, respectively. In DMSO, the cis-configuration adopts a compact sandwich conformation in which the Tyr and Trp aromatic rings pack against the proline ring, whereas the trans-configuration adopts an extended conformation. Although non-random structure was not observed in water, condensed phase molecular dynamics calculations indicate that trans-isomers dominate the population in this higher dielectric medium. Structural comparison of the cis-and trans-configurations with morphine and selective W Wpeptide ligands PL-017 and D-TIPP, as well as the N N-selective peptide ligands TIPP (N N-antagonist, W W-agonist) and DPDPE were also performed and suggest the trans-isomer is likely the bioactive form. A hypothesis is proposed to explain W W-and N Nselectivity based on the presence of spatially distinct selectivity pockets among these ligands.z 1998 Federation of European Biochemical Societies.

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Section: Discussionmentioning

confidence: 95%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Conformational analysis of the endogenous μ‐opioid agonist endomorphin‐1 using NMR spectroscopy and molecular modeling

Podlogar¹,

et al. 1998

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“…Opioid antagonists are generally obtained by substitution of a proton of the basic nitrogen of the tyramine moiety, common to all opioids, with an appropriate substituent, generally an allyl or a cyclopropylmethyl group. The first exception to this rule was furnished by the discovery [1]of two δ selective peptide antagonists related to dermorphin but containing l ‐Tic (1,2,3,4‐tetrahydroisoquinoline‐3‐carboxylic acid) in the second position: Tyr‐Tic‐Phe‐NH 2 (dubbed TIP) and Tyr‐Tic‐Phe‐Phe‐NH 2 (dubbed TIPP).…”

Section: Introductionmentioning

confidence: 99%

Design of μ selective opioid dipeptide antagonists

Capasso

Amodeo²,

Balboni

et al. 1997

FEBS Letters

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We have recently designed potent delta selective opioid antagonist dipeptides on the basis of a simple conformational analysis. Following a similar procedure we found a mu selective dipeptide antagonist, 2,6-dimethyl-Tyr-D-Phe-NH2. Although its selectivity is not as high as those of the quoted delta selective dipeptides it has good in vitro activity and looks very promising for further development since the 2,6-dimethyl-Tyr-D-Phe message, like the delta selective 2,6-dimethyl-Tyr-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid counterpart, seems able to impart antagonism to longer peptides.

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“…We have adapted the strategy pioneered by those interested in defining bioactive conformations of peptide hormones (22, 23) to prepare a conformationally constrained version of phenylazo‐phenylalanine. We report here a straightforward synthesis of the amino acid phenylazo‐1,2,3,4‐tetrahydro‐3‐isoquinolinecarboxylic acid (PATIC) and show that this amino acid can be incorporated into peptides via standard Fmoc‐based solid phase peptide synthesis techniques.…”

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confidence: 99%

PATIC: a conformationally constrained photoisomerizable amino acid

Zhang

James

Woolley

1999

The Journal of Peptide Research

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The synthesis of a conformationally constrained photoisomerizable amino acid, phenylazo-1,2,3,4-tetrahydro-3-isoquinolinecarboxylic acid (PATIC), is described. This amino acid can be incorporated into peptides using standard Fmoc procedures and can be accommodated within alpha-helical structures albeit with some loss of stability of the structure. PATIC can serve as a useful building block for the synthesis of photoregulated peptides and proteins.

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The Use of Conformational Restriction and Molecular Modeling Techniques in the Development of Receptor-Specific Opioid Peptide Agonists and Antagonists

Cited by 4 publications

References 0 publications

Conformational analysis of the endogenous μ‐opioid agonist endomorphin‐1 using NMR spectroscopy and molecular modeling

Conformational analysis of the endogenous μ‐opioid agonist endomorphin‐1 using NMR spectroscopy and molecular modeling

Design of μ selective opioid dipeptide antagonists

PATIC: a conformationally constrained photoisomerizable amino acid

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