X-RAY STRUCTURE OF [D-PEN(2),D-PEN(5)]ENKEPHALIN, A HIGHLY POTENT, DELTA-OPIOID RECEPTOR-SELECTIVE COMPOUND - COMPARISONS WITH PROPOSED SOLUTION CONFORMATIONS

被引:65
作者
FLIPPENANDERSON, JL
HRUBY, VJ
COLLINS, N
GEORGE, C
CUDNEY, B
机构
[1] HAMPTON RES,RIVERSIDE,CA 92507
[2] UNIV ARIZONA,DEPT CHEM,TUCSON,AZ 85721
关键词
D O I
10.1021/ja00096a008
中图分类号
O6 [化学];
学科分类号
0703 ;
摘要
[D-Pen(2), D-Pen(5)]enkephalin (DPDPE), a cyclic, constrained, highly potent, and delta opioid receptor-selective analogue of enkephalin, has been obtained from an aqueous solution in a crystalline form suitable for X-ray analysis. It crystallizes in the triclinic space group P1. The unit cell contains three conformationally distinct molecules of DPDPE which are located with approximate 3-fold symmetry about a water channel made up of approximately 24 disordered and one ordered water molecules. There are also 13 ordered water molecules which form an intricate network of hydrogen bonds which hold the peptide molecules together in the crystal. The conformation of the 14-membered ring is essentially identical for all three molecules; however, the Tyr-1 residue is conformationally different in each case. Comparison of the conformations found in the crystal with those previously determined by NMR methods in conjunction with energy calculations indicates that the most favorable conformation of the 14-membered ring in aqueous solution is similar to that in the crystal. This was interpreted to be due to the cyclic constraint in DPDPE and the high degree of solvation in the crystal structure. In addition, low-energy conformations previously determined by computational methods in attempts to determine the binding conformations of DPDPE gave conformations of the 14-membered rings which were generally similar to those found in the crystal structure. These results and previous structure-activity relationships suggest that the solid-state conformations are a useful starting point for understanding the bioactive conformation important for biological activity and delta receptor selectivity of cyclic enkephalin analogues.
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页码:7523 / 7531
页数:9
相关论文
共 48 条
  • [1] AMICHE M, 1989, MOL PHARMACOL, V35, P774
  • [2] [Anonymous], 1984, PEPTIDES ANAL SYNTHE
  • [3] BALARAM P, 1984, P INDIAN ACAD SCI CH, V93, P707
  • [4] CHEW C, 1991, MOL PHARMACOL, V39, P502
  • [5] CHARACTERIZATION OF THE BIOACTIVE FORM AND MOLECULAR DETERMINANTS OF RECOGNITION OF CYCLIC ENKEPHALIN PEPTIDES AT THE DELTA-OPIOID RECEPTOR
    CHEW, C
    VILLAR, HO
    LOEW, GH
    [J]. BIOPOLYMERS, 1993, 33 (04) : 647 - 657
  • [6] DELTORPHINS - A FAMILY OF NATURALLY-OCCURRING PEPTIDES WITH HIGH-AFFINITY AND SELECTIVITY FOR DELTA-OPIOID BINDING-SITES
    ERSPAMER, V
    MELCHIORRI, P
    FALCONIERIERSPAMER, G
    NEGRI, L
    CORSI, R
    SEVERINI, C
    BARRA, D
    SIMMACO, M
    KREIL, G
    [J]. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1989, 86 (13) : 5188 - 5192
  • [7] FREIDINGER RM, 1984, ACS SYM SER, V251, P169
  • [8] CONFORMATIONAL SEARCH IN ENKEPHALIN ANALOGS CONTAINING A DISULFIDE BOND
    FROIMOWITZ, M
    [J]. BIOPOLYMERS, 1990, 30 (11-12) : 1011 - 1025
  • [9] FROIMOWITZ M, 1989, INT J PEPT PROT RES, V34, P88
  • [10] GRIFIN J, 1988, NIDA RES MONOGR, V87, P48