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

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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
Publication statusPublished - 1992

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ASJC Scopus subject areas

  • Biochemistry

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