Synthesis and opioid activity of dynorphin A-(1-13)NH2 analogues containing cis- and trans-4-aminocyclohexanecarboxylic acid

Kristin R. Snyder, Thomas F. Murray, Gary E. DeLander, Jane V. Aldrich

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Abstract

It has been proposed that the "message" sequence of dynorphin A (Dyn A) exists in an extended conformation in aqueous solution (Schiller, P. W. Int. J. Pept. Protein Res. 1983, 21, 307-312). Molecular modeling suggested that trans-4-aminocyclohexanecarboxylic acid (trans-ACCA) might function as a conformationally constrained replacement for Gly2-Gly3 of Dyn A in such an extended conformation. ACCA was synthesized by catalytic hydrogenation of p-aminobenzoic acid, and the cis and trans isomers were separated by fractional recrystallization. Analogues of Dyn A-(1-13)-NH2 containing cis- and trans-ACCA were prepared by solid-phase peptide synthesis using the Fmoc chemical protocol. Results from radioligand binding assays indicated that the peptides have modest affinity for κ opioid receptors (Ki's = 9.1 and 13.4 nM for [cis-ACCA2-3]- and [trans-ACCA2-3]Dyn A-(1-13)NH2, respectively) and modest κ-receptor selectivity (Ki ratio (κ/ μ/δ) = 1/13/210 and 1/21/103, respectively). [cis-ACCA2-3]- and [trans-ACCA2-3]Dyn A-(1-13)-NH2 are the first reported Dyn A analogues constrained in the "message" sequence that are selective for κ receptors. The cis-ACCA analogue showed very weak opioid activity (IC50 = 4.0 μM) in the guinea pig ileum.

Original languageEnglish
Pages (from-to)1100-1103
Number of pages4
JournalJournal of Medicinal Chemistry
Volume36
Issue number8
StatePublished - 1993
Externally publishedYes

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Dynorphins
Opioid Analgesics
Conformations
4-Aminobenzoic Acid
Radioligand Assay
Peptides
Solid-Phase Synthesis Techniques
Molecular modeling
Hydrogenation
Opioid Receptors
Ileum
Isomers
Inhibitory Concentration 50
Assays
Guinea Pigs
dynorphin (1-13)
4-aminocyclohexanecarboxylic acid
Proteins

All Science Journal Classification (ASJC) codes

  • Organic Chemistry

Cite this

Synthesis and opioid activity of dynorphin A-(1-13)NH2 analogues containing cis- and trans-4-aminocyclohexanecarboxylic acid. / Snyder, Kristin R.; Murray, Thomas F.; DeLander, Gary E.; Aldrich, Jane V.

In: Journal of Medicinal Chemistry, Vol. 36, No. 8, 1993, p. 1100-1103.

Research output: Contribution to journalArticle

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