jm0310028_si_001.pdf (162.14 kB)
Structure−Activity Study on the Phe Side Chain Arrangement of Endomorphins Using Conformationally Constrained Analogues
journal contribution
posted on 2004-01-29, 00:00 authored by Csaba Tömböly, Katalin E. Kövér, Antal Péter, Dirk Tourwé, Dauren Biyashev, Sándor Benyhe, Anna Borsodi, Mahmoud Al-Khrasani, András Z. Rónai, Géza TóthEndomorphins-1 and -2 were substituted with all the β-MePhe stereoisomers in their Phe
residues to generate a conformationally constrained peptide set. This series of molecules was
subjected to biological assays, and for β-MePhe4-endomorphins-2, a conformational analysis
was performed. Incorporation of (2S,3S)-β-MePhe4 resulted in the most potent analogues of
both endomorphins with enhanced enzymatic stability. Their μ opioid affinities were 4-times
higher than the parent peptides, they stimulated [35S]GTPγS binding, and they were found to
be full agonists. NMR experiments revealed that C-terminal (2S,3S)-β-MePhe in endomorphin-2
strongly favored the gauche (−) spatial orientation which implies the presence of the χ =
−60° rotamer of Phe4 in the binding conformer of endomorphins. Our results emphasize that
the appropriate orientation of the C-terminal aromatic side chain of endomorphins is substantial
for binding to the μ opioid receptor.