title: Structure-activity study on the spatial arrangement of the third aromatic ring of endomorphins 1 and 2 using an atypical constrained C terminus.
abstract: The discovery of endomorphins (EMs) has opened the possibility of searching for new analgesics. However, the design of peptide analgesics has proven to be very difficult as a result of their conformational flexibility and a lack of clarity in structure-activity relationships (SAR). In EMs, the amino acid side chains exhibit considerable conformational flexibility, especially in the third aromatic ring, which is free to adopt a bioactive conformation. To resolve these problems, a series of C terminus EM analogues, [Xaa(4)-R]EMs, modified through the substitution of Phe(4) with nonaromatic residues and termination with benzyl groups, were designed to generate conformational constrains of the third aromatic ring by amide bond and torsion angles (phi(4) and psi(4)) of Xaa(4). Introduction of (S)-alpha-methyl or (S)/(R)-alpha-carboxamide on the methylene unit of the benzyl group was designed to produce an atypical topographical constraint (phi(5)) of the third aromatic ring rotation. Interestingly, some EM derivatives, with elimination of the C-terminal carboxamide group and significant changes in the address sequence (Phe(4)-NH(2)), still exhibited higher mu-opioid receptor (MOR) affinity than unmodified EMs. In contrast, some analogues with incorrectly constrained C termini displayed very low affinity and pharmacological activities. Thus, our results indicate that these EM analogues, with atypical constrained C termini, provide model compounds with potent MOR agonism. They also give evidence that the proper spatial orientation and conformational restriction of the third aromatic ring are crucial for the interaction of EMs with MOR.
authors.affiliation: Institute of Biochemistry and Molecular Biology, State Key Laboratory of Applied Organic Chemistry, Lanzhou University, 222 Tian Shui South Road, Lanzhou 730000, China.
authors.forename: Ye
authors.initials: Y
authors.lastname: Yu
authors.forename: Xuan
authors.initials: X
authors.lastname: Shao
authors.forename: Yun
authors.initials: Y
authors.lastname: Cui
authors.forename: Hong-mei
authors.initials: HM
authors.lastname: Liu
authors.forename: Chang-ling
authors.initials: CL
authors.lastname: Wang
authors.forename: Ying-zhe
authors.initials: YZ
authors.lastname: Fan
authors.forename: Jing
authors.initials: J
authors.lastname: Liu
authors.forename: Shou-liang
authors.initials: SL
authors.lastname: Dong
authors.forename: Yu-xing
authors.initials: YX
authors.lastname: Cui
authors.forename: Rui
authors.initials: R
authors.lastname: Wang
mesh_terms: D000577:Amides / Q000737:chemistry; D000595:Amino Acid Sequence; D000701:Analgesics, Opioid / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D015195:Drug Design; D006168:Guinea Pigs; D006841:Hydrocarbons, Aromatic / Q000737:chemistry*; D007082:Ileum / Q000187:drug effects* / Q000502:physiology; D008297:Male; D051379:Mice; D008969:Molecular Sequence Data; D009842:Oligopeptides / Q000737:chemistry / Q000494:pharmacology*; D011487:Protein Conformation; D011957:Receptors, Opioid / Q000819:agonists / Q000378:metabolism*; D017450:Receptors, Opioid, mu / Q000819:agonists / Q000378:metabolism; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014649:Vas Deferens / Q000187:drug effects / Q000502:physiology
chemical_list: D000577:Amides; D000701:Analgesics, Opioid; D006841:Hydrocarbons, Aromatic; D009842:Oligopeptides; D011957:Receptors, Opioid; D017450:Receptors, Opioid, mu; C105293:endomorphin 1; C105294:endomorphin 2