title: Structure-activity study on the Phe side chain arrangement of endomorphins using conformationally constrained analogues.
abstract: Endomorphins-1 and -2 were substituted with all the beta-MePhe stereoisomers in their Phe residues to generate a conformationally constrained peptide set. This series of molecules was subjected to biological assays, and for beta-MePhe(4)-endomorphins-2, a conformational analysis was performed. Incorporation of (2S,3S)-beta-MePhe(4) resulted in the most potent analogues of both endomorphins with enhanced enzymatic stability. Their micro opioid affinities were 4-times higher than the parent peptides, they stimulated [(35)S]GTPgammaS binding, and they were found to be full agonists. NMR experiments revealed that C-terminal (2S,3S)-beta-MePhe in endomorphin-2 strongly favored the gauche (-) spatial orientation which implies the presence of the chi(1) = -60 degrees rotamer of Phe(4) 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 micro opioid receptor.
authors.affiliation: Institute of Biochemistry, Biological Research Center of the Hungarian Academy of Sciences, 6701 Szeged, P.O. Box 521, Hungary.
authors.forename: Csaba
authors.initials: C
authors.lastname: Tömböly
authors.forename: Katalin E
authors.initials: KE
authors.lastname: Kövér
authors.forename: Antal
authors.initials: A
authors.lastname: Péter
authors.forename: Dirk
authors.initials: D
authors.lastname: Tourwé
authors.forename: Dauren
authors.initials: D
authors.lastname: Biyashev
authors.forename: Sándor
authors.initials: S
authors.lastname: Benyhe
authors.forename: Anna
authors.initials: A
authors.lastname: Borsodi
authors.forename: Mahmoud
authors.initials: M
authors.lastname: Al-Khrasani
authors.forename: András Z
authors.initials: AZ
authors.lastname: Rónai
authors.forename: Géza
authors.initials: G
authors.lastname: Tóth
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism; D066298:In Vitro Techniques; D009682:Magnetic Resonance Spectroscopy; D008968:Molecular Conformation; D009842:Oligopeptides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D017208:Rats, Wistar; D017450:Receptors, Opioid, mu / Q000819:agonists; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D009842:Oligopeptides; D017450:Receptors, Opioid, mu; C105293:endomorphin 1; C105294:endomorphin 2