Newly Discovered Stereochemical Requirements in the Side-Chain Conformation of δ Opioid Agonists for Recognizing Opioid δ Receptors

Xinhua Qian, Katalin E. Kövér, Mark D. Shenderovich, Bih Show Lou, Aleksandra Misicka, Teresa Zalewska, Robert Horváth, Peg Davis, E. J. Bilsky, Frank Porreca, Henry I. Yamamura, Victor J. Hruby

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Abstract

Topographic design of peptide ligands using specialized topographically constrained amino acids can provide new insights into the stereochemical requirements for δ opioid receptors. A highly constrained tyrosine derivative, (2S,3S)-β-methyl-2′,6′-dimethyltyrosine [(2S,3S)-TMT], was prepared by asymmetric synthesis and incorporated in [D-Pen2,D-Pen5]enkephalin (δ1) and Deltorphin I (δ2). The results of binding assays and bioassays showed that the two analogues (3 and 4) acted very differently at δ opioid receptors. Further pharmacological evaluations suggested that they actually interact primarily with the δ1 and δ2 receptor subtypes, respectively. These results, and conformational studies using NMR and computer-assisted modeling, provided insights into the different stereochemical requirements opioid receptor and its subtypes.

Original languageEnglish
Pages (from-to)1746-1757
Number of pages12
JournalJournal of Medicinal Chemistry
Volume37
Issue number12
DOIs
Publication statusPublished - Jun 1 1994

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ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

Cite this

Qian, X., Kövér, K. E., Shenderovich, M. D., Lou, B. S., Misicka, A., Zalewska, T., Horváth, R., Davis, P., Bilsky, E. J., Porreca, F., Yamamura, H. I., & Hruby, V. J. (1994). Newly Discovered Stereochemical Requirements in the Side-Chain Conformation of δ Opioid Agonists for Recognizing Opioid δ Receptors. Journal of Medicinal Chemistry, 37(12), 1746-1757. https://doi.org/10.1021/jm00038a004