New endomorphin analogues containing alicyclic β-amino acids: Influence on bioactive conformation and pharmacological profile

Attila Keresztes, Mária Szucs, Attila Borics, Katalin E. Kövér, Eniko Forró, Ferenc Fülöp, Csaba Tömböly, Antal Péter, Annamária Páhi, Gabriella Fábián, Mariann Murányi, Géza Tóth

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Abstract

Endomorphins were subjected to a number of structural modifications in a search for their bioactive conformations. The alicyclic β-amino acids cis-(1S,2R)ACPC/ACHC, cis-(1R,2S)ACPC/ACHC, trans(1S,25)ACPC/ACHC, and trans-(1R,2R)ACPC/ACHC were introduced into endomorphins to examine the conformational effects on the bioactivity. Use of a combination of receptor binding techniques, 1H NMR, and molecular modeling allowed the conclusion that Pro2 substitution by these residues causes changes in structure, proteolytic stability, and pharmacological activity. It seems that the size of the alicyclic β-amino acids does not have marked influence on the receptor binding affinities and/or selectivities. Among the new analogues, the cis-(1S,2R)ACPC2 and cis-(1S,2R)ACHC2-containing derivatives displayed the highest binding potencies and efficacies in receptor binding and ligand-stimulated [35S]GTPγS functional experiments. Molecular dynamic simulations and 1H NMR studies of the cis-ACPC/ACHC-containing analogues revealed that many conformations are accessible, though it is most likely that these peptides bind to the μ-opioid receptor in a compact, folded structure rather than extended.

Original languageEnglish
Pages (from-to)4270-4279
Number of pages10
JournalJournal of Medicinal Chemistry
Volume51
Issue number14
DOIs
Publication statusPublished - Jul 24 2008

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ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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