title: Side chain modifications change the binding and agonist properties of endomorphin 2.
abstract: Side chain modifications were introduced to endomorphin 2 (E2) to improve its binding properties and biological activity. A number of C-terminal modifications decreased the binding affinity to the mu-opioid receptor and the intrinsic activity in rat brain membranes. The exception was E2-ol, which showed increased binding affinity to MOR and higher potency in stimulating [(35)S]GTPgammaS binding. N-methylation of Phe(3) (MePhe(3)) attenuated the binding affinity and produced a rightward shift of [(35)S]GTPgammaS binding curves. All derivatives had lower intrinsic activity than E2. Some of the modified peptides partially inhibited, while YPF-benzyl-allyl-amide fully inhibited, the E2 or [d-Ala(2),MePhe(4),Gly(5)ol]enkephalin stimulated [(35)S]GTPgammaS binding. Marked differences were found between the results obtained using tritiated E2, tritiated naloxone, and [(35)S]GTPgammaS binding, indicating the possible involvement of multiple binding sites. The data presented demonstrate that the C-terminal amide group has an essential role in the regulation of the binding and the agonist/antagonist properties of E2.
authors.affiliation: Institute of Biochemistry, Biological Research Centre, Hungarian Academy of Sciences, P.O. Box 521, H-6701 Szeged, Hungary. ilengyel@nucleus.szbk.u-szeged.hu
authors.forename: I
authors.initials: I
authors.lastname: Lengyel
authors.forename: G
authors.initials: G
authors.lastname: Orosz
authors.forename: D
authors.initials: D
authors.lastname: Biyashev
authors.forename: L
authors.initials: L
authors.lastname: Kocsis
authors.forename: M
authors.initials: M
authors.lastname: Al-Khrasani
authors.forename: A
authors.initials: A
authors.lastname: Rónai
authors.forename: Cs
authors.initials: C
authors.lastname: Tömböly
authors.forename: Zs
authors.initials: Z
authors.lastname: Fürst
authors.forename: G
authors.initials: G
authors.lastname: Tóth
authors.forename: A
authors.initials: A
authors.lastname: Borsodi
mesh_terms: D000818:Animals; D001665:Binding Sites; D001921:Brain / Q000378:metabolism; D002462:Cell Membrane / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D020128:Inhibitory Concentration 50; D007700:Kinetics; D008024:Ligands; D008956:Models, Chemical; D016297:Mutagenesis, Site-Directed; D009270:Naloxone / Q000494:pharmacology; D009842:Oligopeptides / Q000737:chemistry* / Q000378:metabolism*; D010455:Peptides / Q000737:chemistry; D011485:Protein Binding; D011487:Protein Conformation; D017434:Protein Structure, Tertiary; D051381:Rats; D017208:Rats, Wistar; D017450:Receptors, Opioid, mu / Q000737:chemistry
chemical_list: D008024:Ligands; D009842:Oligopeptides; D010455:Peptides; D017450:Receptors, Opioid, mu; D009270:Naloxone; C105294:endomorphin 2