Pharmacological and chemical properties of astressin, antisauvagine-30 and α-helCRF:: significance for behavioral experiments

被引:28
作者
Brauns, O [1 ]
Liepold, T [1 ]
Radulovic, J [1 ]
Spiess, J [1 ]
机构
[1] Max Planck Inst Expt Med, Dept Mol Neuroendocrinol, D-37075 Gottingen, Germany
关键词
CRF; CRF receptor; astressin; antisauvagine-30; alpha-helical CRF; Schild analysis; behavior;
D O I
10.1016/S0028-3908(01)00094-6
中图分类号
Q189 [神经科学];
学科分类号
071006 ;
摘要
Corticotropin releasing factor (CRF) represents an early chemical signal in the stress response and modulates various brain functions through G protein-coupled receptors. Two CRF receptor subtypes, CRF1 and CRF2, have been identified. Since the physicochemical properties of CRF receptor antagonists might influence their biological potency, the peptidic antagonists astressin, alpha -helical CRF9-41 (alpha -helCRF) and antisauvagine-30 (aSvg-30) have been analyzed. The rank order of solubility of these compounds in artificial cerebrospinal fluid (aCSF, pH 7.4) was aSvg-30 > alpha -helCRF > > astressin, whereas the rank order of relative lipophilicity as determined with RP-HPLC was alpha -helCRF > astressin > aSvg-30. The calculated isoelectric points were 4.1 (alpha -helCRF), 7.4 (astressin) and 10.0 (aSvg-30). According to Schild analysis of the CRF receptor-dependent cAMP production of transfected HEK cells, aSvg-30 exhibited a competitive antagonism and displayed a 340 fold selectivity for mCRF(2 beta) receptor. For astressin, however, the pharmacodynamic profile could not be explained by a simple competitive mechanism as indicated by Schild slopes > 1 for rCRF(1) or mCRF(2 beta) receptor. Behavioral experiments demonstrated that after i.c.v. injection, alpha -helCRF reduced oCRF-induced anxiety-like behavior tn the elevated plus-maze, whereas astressin, despite its higher in vitro potency, did not. These findings could be explained by different physicochemical properties of the antagonists employed. (C) 2001 Elsevier Science Ltd. All rights reserved.
引用
收藏
页码:507 / 516
页数:10
相关论文
共 47 条
  • [21] LEDERIS K, 1982, P W PHARMACOL SOC, V25, P223
  • [22] CLONING AND CHARACTERIZATION OF A FUNCTIONALLY DISTINCT CORTICOTROPIN-RELEASING FACTOR-RECEPTOR SUBTYPE FROM RAT-BRAIN
    LOVENBERG, TW
    LIAW, CW
    GRIGORIADIS, DE
    CLEVENGER, W
    CHALMERS, DT
    DESOUZA, EB
    OLTERSDORF, T
    [J]. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1995, 92 (03) : 836 - 840
  • [24] Astressin, a novel and potent CRF antagonist, is neuroprotective in the hippocampus when administered after a seizure
    Maecker, H
    Desai, A
    Dash, R
    Rivier, J
    Vale, W
    Sapolsky, R
    [J]. BRAIN RESEARCH, 1997, 744 (01) : 166 - 170
  • [25] MENZAGHI F, 1994, J PHARMACOL EXP THER, V269, P564
  • [26] Constrained corticotropin-releasing factor antagonists with i-(i+3) Glu-Lys bridges
    Miranda, A
    Lahrichi, SL
    Gulyas, J
    Koerber, SC
    Craig, AG
    Corrigan, A
    Rivier, C
    Vale, W
    Rivier, J
    [J]. JOURNAL OF MEDICINAL CHEMISTRY, 1997, 40 (22) : 3651 - 3658
  • [27] The significance of artificial cerebrospinal fluid as perfusate and endoneurosurgery
    Oka, K
    Yamamoto, M
    Nonaka, T
    Tomonaga, M
    [J]. NEUROSURGERY, 1996, 38 (04) : 733 - 736
  • [28] THE DISTRIBUTION OF CORTICOTROPIN RELEASING FACTOR-LIKE IMMUNOREACTIVE NEURONS IN RAT-BRAIN
    OLSCHOWKA, JA
    ODONOHUE, TL
    MUELLER, GP
    JACOBOWITZ, DM
    [J]. PEPTIDES, 1982, 3 (06) : 995 - 1015
  • [29] OWENS MJ, 1991, PHARMACOL REV, V43, P425
  • [30] The first extracellular domain of corticotropin releasing factor-R1 contains major binding determinants for urocortin and astressin
    Perrin, MH
    Sutton, S
    Bain, DL
    Berggren, WT
    Vale, WW
    [J]. ENDOCRINOLOGY, 1998, 139 (02) : 566 - 570