Synthesis and opioid activity of conformationally constrained dynorphin A analogues. 1. Conformational constraint in the "message" sequence

Seksiri Arttamangkul, Thomas F. Murray, Gary E. DeLander, Jane V. Aldrich

Research output: Contribution to journalArticle

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Abstract

A constrained analogue of the opioid peptide dynorphin A (Dyn A) cyclized in the "message" sequence was designed which may be compatible with the helical conformation proposed by Schwyzer (Biochemistry 1986, 25, 4281-4286) as the conformation Dyn A adopts at κ opioid receptors. On the basis of molecular modeling with AMBER, we prepared the lactam cyclo-[D-Asp2,Dap5]Dyn A-(1-13)NH2 (1; Dap = α,β-diaminopropionic acid) containing a four-atom bridge between positions 2 and 5 as a possible constraint compatible with an α-helix, along with the homologues with five- (2) and six-atom (3) bridges containing Dab (α,γ-diaminobutyric acid) and Orn, respectively, in position 5. All of the cyclic peptide analogues exhibited high binding affinity for both κ and μ receptors and high potency in the guinea pig ileum (GPI) assay. As ring size increased, a trend in receptor selectivity from slightly κ selective (compound 1) to nonselective for κ vs μ (compound 2) to slightly μ selective (compound 3) was observed in the radioligand binding assays. The results in the GPI for antagonism of these peptides by naloxone paralleled the results of the binding assays and indicated that compound 1 preferentially interacted with κ receptors in this tissue. Novel byproducts were also obtained from the cyclization reactions with HBTU (2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate) and characterized as [D-Asp2,X(Tmg)5]Dyn A-(1-13)NH2 (where X = Dap, Dab, or Orn and Tmg = tetramethylguanidinium). All of the Tmg linear byproducts bound with high affinity to κ and μ receptors and also exhibited potent agonist activity in the GPI. Circular dichroism spectra of compound 1 and the parent peptide Dyn A-(1-13)NH2 determined in 80% trifluoroethanol at 5°C were consistent with some α-helical content in the peptides; comparison of the Δε at 222 nm suggested that compound 1 possessed slightly higher helical content than Dyn A-(1-13)NH2 under these experimental conditions. The cyclic Dyn A analogues 1-3 described here represent the first Dyn A analogues constrained in the "message" sequence with demonstrated high affinity and potency at κ receptors.

Original languageEnglish (US)
Pages (from-to)2410-2417
Number of pages8
JournalJournal of Medicinal Chemistry
Volume38
Issue number13
StatePublished - 1995
Externally publishedYes

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Dynorphins
Opioid Analgesics
Ileum
Assays
Guinea Pigs
Peptides
Acids
Byproducts
Conformations
Trifluoroethanol
Lactams
Atoms
Cyclic Peptides
Radioligand Assay
Biochemistry
Molecular modeling
Opioid Peptides
Cyclization
Opioid Receptors
Naloxone

ASJC Scopus subject areas

  • Organic Chemistry

Cite this

Synthesis and opioid activity of conformationally constrained dynorphin A analogues. 1. Conformational constraint in the "message" sequence. / Arttamangkul, Seksiri; Murray, Thomas F.; DeLander, Gary E.; Aldrich, Jane V.

In: Journal of Medicinal Chemistry, Vol. 38, No. 13, 1995, p. 2410-2417.

Research output: Contribution to journalArticle

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