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

Keresztes, A [Keresztes, Attila (biokémia), author] Institute of Biochemistry (SZBK); Szucs, M [Szűcs, Mária (Receptorológia, b...), author] Institute of Biochemistry (SZBK); Borics, A [Borics, Attila (Peptid- és fehérj...), author] Institute of Biochemistry (SZBK); Kover, KE [E Kövér, Katalin (NMR spektroszkópia), author] Department of Inorganic and Analytical Chemistry (UD / IChem); Forro, E [Forró, Enikő (Szerves kémia), author] Department of Pharmaceutical Chemistry (USZ / FP); Fulop, F [Fülöp, Ferenc (Kémia), author] Department of Pharmaceutical Chemistry (USZ / FP); Tomboly, C [Tömböly, Csaba (Peptidkémia, radi...), author] Institute of Biochemistry (SZBK); Peter, A [Péter, Antal (Kromatográfia), author] Department of Inorganic and Analytical Chemistry (USZ / TTIK / KTCS); Pahi, A; Fabian, G [Fábián, Gabriella (biokémia), author] Institute of Biochemistry (SZBK); Muranyi, M; Toth, G ✉ [Tóth, Géza (Radiokémia), author] Institute of Biochemistry (SZBK)

English Scientific Article (Journal Article)
Published: JOURNAL OF MEDICINAL CHEMISTRY 0022-2623 1520-4804 51 (14) pp. 4270-4279 2008
  • SJR Scopus - Drug Discovery: D1
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    Endomorphins were subjected to a number of structural modifications in a search for their bioactive conformations. The alicyclic beta-amino acids cis-(1S,2R)ACPC/ACHC, cis-(IR,2S)ACPC/ACHC, trans(IS,2S)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, H-1 NMR, and molecular modeling allowed the conclusion that Pro(2) substitution by these residues causes changes in structure, proteolytic stability, and pharmacological activity. It seems that the size of the alicyclic beta-amino acids does not have marked influence on the receptor binding affinities and/or selectivities. Among the new analogues, the cis-(1S,2R)ACPC(2) and cis-(1S,2R)ACHC(2)-containing derivatives displayed the highest binding potencies and efficacies in receptor binding and ligand-stimulated [S-35]GTP gamma S functional experiments. Molecular dynamic simulations and H-1 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 mu-opioid receptor in a compact, folded structure rather than extended.
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    2021-11-30 10:20