STEREOSPECIFICITY OF AMINO-ACID SIDE-CHAINS IN DELTORPHIN DEFINES BINDING TO OPIOID RECEPTORS

被引:40
作者
LAZARUS, LH [1 ]
SALVADORI, S [1 ]
BALBONI, G [1 ]
TOMATIS, R [1 ]
WILSON, WE [1 ]
机构
[1] UNIV FERRARA,DEPT PHARMACEUT SCI,I-44100 FERRARA,ITALY
关键词
D O I
10.1021/jm00085a009
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
A series of individual D-amino acid replacement analogues of deltorphin A, several of which were in combination with a His4 deletion, were used to probe alterations of side-chain orientation on peptide binding parameters with rat brain opioid receptors. Peptides with D-amino acids in residues 1, 3, and 5 exhibited diminished affinities primarily for delta-receptors (88-1200-fold) with selectivity decreasing by factors of 13-64-fold relative to deltorphin A (K(i)delta = 0.45 nM; K(i)mu/K(i)delta = 764): the aromatic side chains Tyr1 and Phe3, which lie in the N-terminal "message" domain and the aryl side chain of Leu5 in the C-terminal "address" domain, appear to play essential roles in conferring high delta-affinity and selectivity. Although D-His4 only decreased delta-affinity by 6-fold and selectivity by a factor of 4, His appears to be involved as an integral component of both domains: [des-His4]deltorphin A and [des-His4] analogues containing consecutive D-amino acid replacements in the remaining residues exhibited weak binding to delta-receptors and poor delta-selectivity. Substitution of D-Met2 in deltorphin A by D-Ala or D-Nle decreased delta-selectivities 3-6-fold through an elevation in mu-affinities; however, the converse replacement, D-Met for D-Ala2 in deltorphin B, diminished beta-selectivity by an order of magnitude only through the loss in delta-affinity. The data show that the high delta-affinity and selectivity of deltorphins correlate with and require a strict stereospecificity of the amino acid residue side chains.
引用
收藏
页码:1222 / 1227
页数:6
相关论文
共 41 条
  • [1] [Anonymous], RECEPTORS
  • [2] [Anonymous], 1972, J BIOL CHEM, V247, P977
  • [3] NEW FEATURES OF THE DELTA-OPIOID RECEPTOR - CONFORMATIONAL PROPERTIES OF DELTORPHIN-I ANALOGS
    BALBONI, G
    MARASTONI, M
    PICONE, D
    SALVADORI, S
    TANCREDI, T
    TEMUSSI, PA
    TOMATIS, R
    [J]. BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 1990, 169 (02) : 617 - 622
  • [4] BARANY G, 1987, INT J PEPT PROT RES, V30, P705
  • [5] A 3-DIMENSIONAL ORTHOGONAL PROTECTION SCHEME FOR SOLID-PHASE PEPTIDE-SYNTHESIS UNDER MILD CONDITIONS
    BARANY, G
    ALBERICIO, F
    [J]. JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, 1985, 107 (17) : 4936 - 4942
  • [6] BECKSICKINGER AG, 1990, INT J PEPT PROT RES, V36, P522
  • [7] THE EFFECTS OF STRUCTURE-CONFORMATION MODIFICATIONS OF MELANOTROPIN ANALOGS ON LEARNING AND MEMORY - D-AMINO-ACID SUBSTITUTED LINEAR AND CYCLIC ANALOGS
    BECKWITH, BE
    TINIUS, TP
    HRUBY, VJ
    ALOBEIDI, F
    SAWYER, TK
    AFFHOLTER, JA
    [J]. PEPTIDES, 1989, 10 (02) : 361 - 368
  • [8] BLANC JP, 1984, J BIOL CHEM, V259, P9549
  • [9] ANTAGONISTS OF SUBSTANCE-P
    CARANIKAS, S
    MIZRAHI, J
    DORLEANSJUSTE, P
    REGOLI, D
    [J]. EUROPEAN JOURNAL OF PHARMACOLOGY, 1982, 77 (2-3) : 205 - 206
  • [10] A 500-MHZ PROTON NUCLEAR-MAGNETIC-RESONANCE STUDY OF MU-OPIOID PEPTIDES IN A SIMULATED RECEPTOR ENVIRONMENT
    CASTIGLIONEMORELLI, MA
    LELJ, F
    PASTORE, A
    SALVADORI, S
    TANCREDI, T
    TOMATIS, R
    TRIVELLONE, E
    TEMUSSI, PA
    [J]. JOURNAL OF MEDICINAL CHEMISTRY, 1987, 30 (11) : 2067 - 2073