Design, synthesis, pharmacological evaluation, and structure-activity study of novel endomorphin analogues with multiple structural modifications

Jayapal Reddy Mallareddy, Attila Borics, Attila Keresztes, Katalin E. Kövér, Dirk Tourwé, Géza Tóth

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26 Citations (Scopus)


This study reports on new proteolytically stable, pharmacologically active endomorphin analogues, incorporating Dmt1, Achc2, pFPhe4, or βMePhe4 unnatural amino acids. Consistent with earlier results, it was found that the analogues carrying Dmt1 and Achc2 residues displayed the highest μ-opioid receptor affinities, depending upon the configuration of the incorporated Achc 2. Combination of such derivatives with pFPhe4 or βMePhe4 yielded further compounds with variable binding potencies. Combined application of Dmt1, cis-(1S,2R)Achc2, and pFPhe4 (compound 16) resulted in the most potent analogue. Ligand stimulated [35S]GTPγS binding assays indicated that the analogues retained their agonist activities and opioid receptor specificities. NMR and molecular modeling studies of the analogues containing βMePhe 4 or pFPhe4 confirmed the predominance of bent structures, however, it is apparent that bent structures are energetically more favored than random/extended structures for all studied compounds.

Original languageEnglish
Pages (from-to)1462-1472
Number of pages11
JournalJournal of Medicinal Chemistry
Issue number5
Publication statusPublished - Mar 10 2011


ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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