CHOLECYSTOKININ PEPTIDOMIMETICS AS SELECTIVE CCK-B ANTAGONISTS - DESIGN, SYNTHESIS, AND IN-VITRO AND IN-VIVO BIOCHEMICAL-PROPERTIES

被引:42
作者
BLOMMAERT, AGS [1 ]
WENG, JH [1 ]
DORVILLE, A [1 ]
MCCORT, I [1 ]
DUCOS, B [1 ]
DURIEUX, C [1 ]
ROQUES, BP [1 ]
机构
[1] UNIV PARIS 05,FAC PHARM,DEPT PHARMACOCHIM MOLEC & STRUCT,CNRS,URA D 1500,INSERM,U266,F-75270 PARIS 06,FRANCE
关键词
D O I
10.1021/jm00072a005
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
Antagonists of cholecystokinin-B (CCK-B) receptors have been shown to alleviate CCK4-induced panic attacks in humans and to potentiate opioid effects in animals. The clinical use of these compounds is critically dependent on their ability to cross the blood-brain barrier. In order to improve this property, new, peptoid-derived CCK-B antagonists, endowed with high affinity, selectivity, and increased lipophilicity have been developed. The affinity and selectivity of these compounds have been characterized in vitro and in vivo using guinea pig, rat, and mouse. Most of these compounds proved to be selective for the CCK-B receptor, the most potent analog, N-[N-[(2-adamantyloxy)carbonyl]-D-alpha-methyltryptophanyl]-N-[2-(4-chlorophenyl)ethyl]glycine (26A), having a K(i) value of 6.1 nM for guinea pig cortex membranes in vitro and a good selectivity ratio (K(i) CCK-A/K(i) CCK-B = 174). Furthermore, the in vivo affinity of 26A for mouse brain CCK-B receptors, following intracerebroventricular injection at different concentrations, was found to be 10 nmol. Using competition experiments with the specific CCK-B ligand [H-3]pBC 264, compound 26A was shown to cross the blood-brain barrier (0.2%) after intraperitoneal administration in mice. This compound is therefore an interesting pharmacological tool to further elucidate the physiopathological role of endogenous CCK.
引用
收藏
页码:2868 / 2877
页数:10
相关论文
共 49 条
  • [1] RESOLUTION OF ALPHA-METHYL AMINO ESTERS BY CHYMOTRYPSIN
    ANANTHARAMAIAH, GM
    ROESKE, RW
    [J]. TETRAHEDRON LETTERS, 1982, 23 (33) : 3335 - 3336
  • [2] BENZODIAZEPINE GASTRIN AND BRAIN CHOLECYSTOKININ RECEPTOR LIGANDS - L-365,260
    BOCK, MG
    DIPARDO, RM
    EVANS, BE
    RITTLE, KE
    WHITTER, WL
    VEBER, DF
    ANDERSON, PS
    FREIDINGER, RM
    [J]. JOURNAL OF MEDICINAL CHEMISTRY, 1989, 32 (01) : 13 - 16
  • [3] BODENPR, 1993, J MED CHEM, V36, P552
  • [4] BOHME A, 1992, N-S ARCH PHARMACOL, V345, pR116
  • [5] BRADWEJN J, 1991, ARCH GEN PSYCHIAT, V48, P603
  • [6] BRADWEJN J, 1992, CLIN NEUROPHARM S1, V15, P9
  • [7] ENZYME-RESISTANT CCK ANALOGS WITH HIGH AFFINITIES FOR CENTRAL RECEPTORS
    CHARPENTIER, B
    DURIEUX, C
    PELAPRAT, D
    DOR, A
    REIBAUD, M
    BLANCHARD, JC
    ROQUES, BP
    [J]. PEPTIDES, 1988, 9 (04) : 835 - 841
  • [8] CHEN IW, 1992, DRUG METAB DISPOS, V20, P390
  • [9] CCK-B AGONIST OR ANTAGONIST ACTIVITIES OF STRUCTURALLY HINDERED AND PEPTIDASE-RESISTANT BOC-CCK4 DERIVATIVES
    CORRINGER, PJ
    WENG, JH
    DUCOS, B
    DURIEUX, C
    BOUDEAU, P
    BOHME, A
    ROQUES, BP
    [J]. JOURNAL OF MEDICINAL CHEMISTRY, 1993, 36 (01) : 166 - 172
  • [10] DANHO W, 1992, INT J PEPT PROT RES, P337