Analogs of lactam derivatives of α-melanotropin with basic and acidic residues

被引:29
作者
Bednarek, MA
MacNeil, T
Kalyani, RN
Tang, R
Van der Ploeg, LHT
Weinberg, DH
机构
[1] Merck Res Labs, Dept Obes & Metab Disorders, Rahway, NJ 07065 USA
[2] Merck Res Labs, Dept Med Chem, Rahway, NJ 07065 USA
关键词
melanotropin; melanocortin receptor; glutamic acid-scan; lysine-scan; binding affinity; cAMP accumulation assay;
D O I
10.1006/bbrc.2000.2589
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
A role of the aromatic and of the basic residues of the potent agonist (MTII) and antagonist (SHU9119) at the human melanocortin receptors 4 in the formation and stabilization of ligand-receptor complexes was examined. Analogs of MTII and SHU9119 with glutamic acid replacing one amino acid at a time were synthesized and tested for their ability to bind to and activate human melanocortin receptors 3, 4, and 5. Replacement of Phe (Na1) or Trp with Glu resulted in analogs of MTII and SHU9119 which were practically inactive at the receptors studied. The rather large (and unexpected) tolerance toward the presence of Glu in the position of His or Arg of MTII and SHU9119 clearly suggested that in the ligand receptor complexes these basic residues are not in contact with the receptors but probably face the extracellular environment. This identified the aromatic residues of MTII and SHU9119 as the primary structural features determining interactions of the agonist/antagonist with hMCR3-5. (C) 2000 Academic Press.
引用
收藏
页码:23 / 28
页数:6
相关论文
共 22 条
  • [11] CYCLIC LACTAM ALPHA-MELANOTROPIN ANALOGS OF AC-NLE(4)-CYCLO[ASP(5),D-PHE(7),LYS(10)] ALPHA-MELANOCYTE-STIMULATING HORMONE-(4-10)-NH2 WITH BULKY AROMATIC-AMINO-ACIDS AT POSITION-7 SHOW HIGH ANTAGONIST POTENCY AND SELECTIVITY AT SPECIFIC MELANOCORTIN RECEPTORS
    HRUBY, VJ
    LU, DS
    SHARMA, SD
    CASTRUCCI, AD
    KESTERSON, RA
    ALOBEIDI, FA
    HADLEY, ME
    CONE, RD
    [J]. JOURNAL OF MEDICINAL CHEMISTRY, 1995, 38 (18) : 3454 - 3461
  • [12] Targeted disruption of the melanocortin-4 receptor results in obesity in mice
    Huszar, D
    Lynch, CA
    FairchildHuntress, V
    Dunmore, JH
    Fang, Q
    Berkemeier, LR
    Gu, W
    Kesterson, RA
    Boston, BA
    Cone, RD
    Smith, FJ
    Campfield, LA
    Burn, P
    Lee, F
    [J]. CELL, 1997, 88 (01) : 131 - 141
  • [13] THE BIO-ORGANIC CHEMISTRY OF ALPHA-MELANOTROPIN
    MEDZIHRADSZKY, K
    [J]. MEDICINAL RESEARCH REVIEWS, 1982, 2 (03) : 247 - 270
  • [14] Physiological regulation of G protein-linked signaling
    Morris, AJ
    Malbon, CC
    [J]. PHYSIOLOGICAL REVIEWS, 1999, 79 (04) : 1373 - 1430
  • [15] A 3-DIMENSIONAL MODEL FOR THE INTERACTION OF MSH WITH THE MELANOCORTIN-1 RECEPTOR
    PRUSIS, P
    FRANDBERG, PA
    MUCENIECE, R
    KALVINSH, I
    WIKBERG, JES
    [J]. BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 1995, 210 (01) : 205 - 210
  • [16] SYNTHESIS AND BIOLOGICAL EVALUATION OF ALPHA-MSH ANALOGS SUBSTITUTED WITH ALANINE
    SAHM, UG
    OLIVIER, GWJ
    BRANCH, SK
    MOSS, SH
    POUTON, CW
    [J]. PEPTIDES, 1994, 15 (07) : 1297 - 1302
  • [17] Characterisation of D117A and H260A mutations in the melanocortin 1 receptor
    Schioth, HB
    Muceniece, R
    Szardenings, M
    Prusis, P
    Lindeberg, G
    Sharma, SD
    Hruby, VJ
    Wikberg, JES
    [J]. MOLECULAR AND CELLULAR ENDOCRINOLOGY, 1997, 126 (02) : 213 - 219
  • [18] Selective properties of C- and N-terminals and core residues of the melanocyte-stimulating hormone on binding to the human melanocortin receptor subtypes
    Schiöth, HB
    Mutulis, F
    Muceniece, R
    Prusis, P
    Wikberg, JES
    [J]. EUROPEAN JOURNAL OF PHARMACOLOGY, 1998, 349 (2-3) : 359 - 366
  • [19] vanRhee AM, 1996, DRUG DEVELOP RES, V37, P1, DOI 10.1002/(SICI)1098-2299(199601)37:1<1::AID-DDR1>3.0.CO
  • [20] 2-S