Design and Synthesis of Highly Potent and Selective Cyclic Dynorphin A Analogs. 2. New Analogs

Andrew M. Kawasaki, Richard J. Knapp, Thomas H. Kramer, Amanda Walton, William S. Wire, Shinicki Hashimoto, Henry I. Yamamura, Frank Porreca, Thomas F. Burks, Victor J. Hruby

Research output: Contribution to journalArticle

24 Scopus citations

Abstract

We have designed and synthesized several cyclic disulfide-containing peptide analogs of dynorphin A (Dyn A) which are conformationally constrained in the putative “address” segment of the opioid ligand. Several of these Dyn A analogs exhibit unexpected apparent selectivities for the κ and μ opioid receptors(s) of the central vs peripheral nervous systems. Thus, incorporation of conformational constraint in the putative “address” segment of Dyn A analogs has resulted in the κ/μ opioid receptor ligands [formula omitted] (4), [formula omitted] (5), [formula omitted] (6), and [formula omitted] (7). All of these analogs possess high κ and μ opioid receptor affinities for the central receptor (guinea pig brain), but effect only weak potency at peripheral κ and μ opioid receptors (GPI). In fact cyclic dynorphin A analog 4 shows >19 000-fold differences between central κ opioid affinity and potency in the guinea pig ileum (GPI). Additionally analog 4 is not an antagonist in the GPI, suggesting possible receptor differences between these sites. Substitution of Tyr1 by Phe1 in the cyclic 1–11 series gave the analog [formula omitted] (1) that was surprisingly potent in the guinea pig brain binding assay (IC50 = 15.1 nM) at the κ receptor, but was inactive in the GPI and mouse vas deferens bioassays. D-Ala2 and Tic4 analogs of 1 had lower affinity at brain κ receptors and had very weak potencies in the GPI and MVD bioassays. On the other hand, [formula omitted] were surprisingly potent in the GPI bioassay, though considerable apparent selectivity for central receptors is still retained. The apparent lack of correlation between the pharmacological profiles observed in smooth muscle and in the brain binding assays, particularly with 1 and 4, may suggest the existence of different subtypes of the κ and μ opioid receptors in the brain and peripheral systems.

Original languageEnglish (US)
Pages (from-to)750-757
Number of pages8
JournalJournal of Medicinal Chemistry
Volume36
Issue number6
DOIs
StatePublished - Jan 1 1993

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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    Kawasaki, A. M., Knapp, R. J., Kramer, T. H., Walton, A., Wire, W. S., Hashimoto, S., Yamamura, H. I., Porreca, F., Burks, T. F., & Hruby, V. J. (1993). Design and Synthesis of Highly Potent and Selective Cyclic Dynorphin A Analogs. 2. New Analogs. Journal of Medicinal Chemistry, 36(6), 750-757. https://doi.org/10.1021/jm00058a012