Cis-4-amino-l-proline residue as a scaffold for the synthesis of cyclic and linear endomorphin-2 analogues: Part 2

Adriano Mollica, Francesco Pinnen, Azzurra Stefanucci, Luisa Mannina, Anatoly P. Sobolev, Gino Lucente, Peg Davis, Josephine Lai, Shou Wu Ma, Frank Porreca, Victor J. Hruby

Research output: Contribution to journalArticle

26 Scopus citations

Abstract

Recently, we reported synthesis and activity of a constrained cyclic analogue of endomorphin-2 (EM-2: Tyr-Pro-Phe-Phe-NH2) and related linear models containing the cis-4-amino-l-proline (cAmp) in place of native Pro2. In the present article, the adopted rationale is the possible modulation of the receptor affinity of the cAmp containing EM-2 analogues by assigning a different stereochemistry to the Phe3 and Phe4 residues present in the ring. Thus, eight more analogues with different absolute configuration at the chiral center of the aromatic residues in positions 3 and 4 have been synthesized and their opioid activity examined. The stereochemical change at the α-carbon atoms leads to a meaningful enhancement of the affinity and activity toward μ opioid receptors with respect to the prototype compound 9: e.g., 9a, Kiμ = 63 nM, GPI (IC50) = 480 nM; 9b, Kiμ = 38 nM, GPI (IC50) = 330 nM.

Original languageEnglish (US)
Pages (from-to)8477-8482
Number of pages6
JournalJournal of Medicinal Chemistry
Volume55
Issue number19
DOIs
StatePublished - Oct 11 2012

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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    Mollica, A., Pinnen, F., Stefanucci, A., Mannina, L., Sobolev, A. P., Lucente, G., Davis, P., Lai, J., Ma, S. W., Porreca, F., & Hruby, V. J. (2012). Cis-4-amino-l-proline residue as a scaffold for the synthesis of cyclic and linear endomorphin-2 analogues: Part 2. Journal of Medicinal Chemistry, 55(19), 8477-8482. https://doi.org/10.1021/jm300947s