Reduced peptide bond cyclic somatostatin based opioid octapeptides. Synthesis, conformational properties and pharmacological characterization

W. M. Kazmierski, R. D. Ferguson, R. J. Knapp, G. K. Lui, H. I. Yamamura, Victor J Hruby

Research output: Contribution to journalArticle

17 Citations (Scopus)

Abstract

The conformational and pharmacological properties that result from peptide bond reduction as well as the use of secondary amino acids in a series of cyclic peptides related to the μ opioid receptor selective antagonist D-Phe1-Cys2-Tyr3-D-Trp4-Orn5-Thr6-Pen7-Thr8-NH2 (IV), have been investigated. Peptide analogues that contain [CH2NH] and [CH2N] pseudo-peptide bonds (in primary and secondary amino acids, respectively) were synthesized on a solid support. Substitution of Tyr3 in IV by the cyclic, secondary amino acid 1,2,3,4-tetrahydroisoquinoline carboxylate (Tic) and of D-Trp4 with D-1,2,3,4-tetrahydro-β-carboline(D-Tca4), gave peptides 4 and 1, respectively. Both analogues displayed reduced affinities for μ opioid receptors. Conformational analysis based on extensive NMR investigations demonstrated that the backbone conformations of 1 and 4 are similar to those of the potent and selective analogue D-Phe-Cys-Tyr-D-Trp-Lys-Thr-Pen-Thr-NH2 (I), while the conformational properties of the side chains of Tic3 (4) and D-Tca4 (1) resulted in topographical properties that were not well recognized by the μ opioid receptor. Peptide bond modifications were made including (Tyr3-ψ[CH2NH]-D-Trp4), 3; (Tyr3-ψ[CH2N]-D-Tca4), 2; and (Cys2-ψ[CH2N]-Tic3), 6. These analogues showed decreases in their μ opioid receptor affinities relative to the parent compounds IV, 1, and 4, respectively. 1H NMR based conformational analysis in conjunction with receptor binding data led to the conclusion that the reduced peptide bonds in 2, 3, 5, and 6 do not contribute to the process of discrimination between μ and δ opioid receptors, and in spite of their different dynamic behaviors (relative to 1 and 4), they are still capable of attaining similar receptor bound conformations, possibly due to their increased flexibility.

Original languageEnglish (US)
Pages (from-to)401-414
Number of pages14
JournalInternational Journal of Peptide and Protein Research
Volume39
Issue number5
StatePublished - 1992

Fingerprint

Somatostatin
Opioid Analgesics
Opioid Receptors
Imino Acids
Pharmacology
Peptides
Conformations
Cyclic Amino Acids
Nuclear magnetic resonance
Carbolines
Cyclic Peptides
Narcotic Antagonists
Substitution reactions

ASJC Scopus subject areas

  • Biochemistry

Cite this

Reduced peptide bond cyclic somatostatin based opioid octapeptides. Synthesis, conformational properties and pharmacological characterization. / Kazmierski, W. M.; Ferguson, R. D.; Knapp, R. J.; Lui, G. K.; Yamamura, H. I.; Hruby, Victor J.

In: International Journal of Peptide and Protein Research, Vol. 39, No. 5, 1992, p. 401-414.

Research output: Contribution to journalArticle

@article{4eefa2b6074948028bbe52e7516ff982,
title = "Reduced peptide bond cyclic somatostatin based opioid octapeptides. Synthesis, conformational properties and pharmacological characterization",
abstract = "The conformational and pharmacological properties that result from peptide bond reduction as well as the use of secondary amino acids in a series of cyclic peptides related to the μ opioid receptor selective antagonist D-Phe1-Cys2-Tyr3-D-Trp4-Orn5-Thr6-Pen7-Thr8-NH2 (IV), have been investigated. Peptide analogues that contain [CH2NH] and [CH2N] pseudo-peptide bonds (in primary and secondary amino acids, respectively) were synthesized on a solid support. Substitution of Tyr3 in IV by the cyclic, secondary amino acid 1,2,3,4-tetrahydroisoquinoline carboxylate (Tic) and of D-Trp4 with D-1,2,3,4-tetrahydro-β-carboline(D-Tca4), gave peptides 4 and 1, respectively. Both analogues displayed reduced affinities for μ opioid receptors. Conformational analysis based on extensive NMR investigations demonstrated that the backbone conformations of 1 and 4 are similar to those of the potent and selective analogue D-Phe-Cys-Tyr-D-Trp-Lys-Thr-Pen-Thr-NH2 (I), while the conformational properties of the side chains of Tic3 (4) and D-Tca4 (1) resulted in topographical properties that were not well recognized by the μ opioid receptor. Peptide bond modifications were made including (Tyr3-ψ[CH2NH]-D-Trp4), 3; (Tyr3-ψ[CH2N]-D-Tca4), 2; and (Cys2-ψ[CH2N]-Tic3), 6. These analogues showed decreases in their μ opioid receptor affinities relative to the parent compounds IV, 1, and 4, respectively. 1H NMR based conformational analysis in conjunction with receptor binding data led to the conclusion that the reduced peptide bonds in 2, 3, 5, and 6 do not contribute to the process of discrimination between μ and δ opioid receptors, and in spite of their different dynamic behaviors (relative to 1 and 4), they are still capable of attaining similar receptor bound conformations, possibly due to their increased flexibility.",
author = "Kazmierski, {W. M.} and Ferguson, {R. D.} and Knapp, {R. J.} and Lui, {G. K.} and Yamamura, {H. I.} and Hruby, {Victor J}",
year = "1992",
language = "English (US)",
volume = "39",
pages = "401--414",
journal = "International Journal of Peptide and Protein Research",
issn = "0367-8377",
publisher = "Wiley-Blackwell",
number = "5",

}

TY - JOUR

T1 - Reduced peptide bond cyclic somatostatin based opioid octapeptides. Synthesis, conformational properties and pharmacological characterization

AU - Kazmierski, W. M.

AU - Ferguson, R. D.

AU - Knapp, R. J.

AU - Lui, G. K.

AU - Yamamura, H. I.

AU - Hruby, Victor J

PY - 1992

Y1 - 1992

N2 - The conformational and pharmacological properties that result from peptide bond reduction as well as the use of secondary amino acids in a series of cyclic peptides related to the μ opioid receptor selective antagonist D-Phe1-Cys2-Tyr3-D-Trp4-Orn5-Thr6-Pen7-Thr8-NH2 (IV), have been investigated. Peptide analogues that contain [CH2NH] and [CH2N] pseudo-peptide bonds (in primary and secondary amino acids, respectively) were synthesized on a solid support. Substitution of Tyr3 in IV by the cyclic, secondary amino acid 1,2,3,4-tetrahydroisoquinoline carboxylate (Tic) and of D-Trp4 with D-1,2,3,4-tetrahydro-β-carboline(D-Tca4), gave peptides 4 and 1, respectively. Both analogues displayed reduced affinities for μ opioid receptors. Conformational analysis based on extensive NMR investigations demonstrated that the backbone conformations of 1 and 4 are similar to those of the potent and selective analogue D-Phe-Cys-Tyr-D-Trp-Lys-Thr-Pen-Thr-NH2 (I), while the conformational properties of the side chains of Tic3 (4) and D-Tca4 (1) resulted in topographical properties that were not well recognized by the μ opioid receptor. Peptide bond modifications were made including (Tyr3-ψ[CH2NH]-D-Trp4), 3; (Tyr3-ψ[CH2N]-D-Tca4), 2; and (Cys2-ψ[CH2N]-Tic3), 6. These analogues showed decreases in their μ opioid receptor affinities relative to the parent compounds IV, 1, and 4, respectively. 1H NMR based conformational analysis in conjunction with receptor binding data led to the conclusion that the reduced peptide bonds in 2, 3, 5, and 6 do not contribute to the process of discrimination between μ and δ opioid receptors, and in spite of their different dynamic behaviors (relative to 1 and 4), they are still capable of attaining similar receptor bound conformations, possibly due to their increased flexibility.

AB - The conformational and pharmacological properties that result from peptide bond reduction as well as the use of secondary amino acids in a series of cyclic peptides related to the μ opioid receptor selective antagonist D-Phe1-Cys2-Tyr3-D-Trp4-Orn5-Thr6-Pen7-Thr8-NH2 (IV), have been investigated. Peptide analogues that contain [CH2NH] and [CH2N] pseudo-peptide bonds (in primary and secondary amino acids, respectively) were synthesized on a solid support. Substitution of Tyr3 in IV by the cyclic, secondary amino acid 1,2,3,4-tetrahydroisoquinoline carboxylate (Tic) and of D-Trp4 with D-1,2,3,4-tetrahydro-β-carboline(D-Tca4), gave peptides 4 and 1, respectively. Both analogues displayed reduced affinities for μ opioid receptors. Conformational analysis based on extensive NMR investigations demonstrated that the backbone conformations of 1 and 4 are similar to those of the potent and selective analogue D-Phe-Cys-Tyr-D-Trp-Lys-Thr-Pen-Thr-NH2 (I), while the conformational properties of the side chains of Tic3 (4) and D-Tca4 (1) resulted in topographical properties that were not well recognized by the μ opioid receptor. Peptide bond modifications were made including (Tyr3-ψ[CH2NH]-D-Trp4), 3; (Tyr3-ψ[CH2N]-D-Tca4), 2; and (Cys2-ψ[CH2N]-Tic3), 6. These analogues showed decreases in their μ opioid receptor affinities relative to the parent compounds IV, 1, and 4, respectively. 1H NMR based conformational analysis in conjunction with receptor binding data led to the conclusion that the reduced peptide bonds in 2, 3, 5, and 6 do not contribute to the process of discrimination between μ and δ opioid receptors, and in spite of their different dynamic behaviors (relative to 1 and 4), they are still capable of attaining similar receptor bound conformations, possibly due to their increased flexibility.

UR - http://www.scopus.com/inward/record.url?scp=0026693088&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0026693088&partnerID=8YFLogxK

M3 - Article

C2 - 1358847

AN - SCOPUS:0026693088

VL - 39

SP - 401

EP - 414

JO - International Journal of Peptide and Protein Research

JF - International Journal of Peptide and Protein Research

SN - 0367-8377

IS - 5

ER -