RATIONALLY DESIGNED DIPEPTOID ANALOGS OF CCK - ALPHA-METHYLTRYPTOPHAN DERIVATIVES AS HIGHLY SELECTIVE AND ORALLY ACTIVE GASTRIN AND CCK-B ANTAGONISTS WITH POTENT ANXIOLYTIC PROPERTIES
RATIONALLY DESIGNED DIPEPTOID ANALOGS OF CCK - ALPHA-METHYLTRYPTOPHAN DERIVATIVES AS HIGHLY SELECTIVE AND ORALLY ACTIVE GASTRIN AND CCK-B ANTAGONISTS WITH POTENT ANXIOLYTIC PROPERTIES
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DOI：
10.1021/jm00105a062
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发表时间：
1991-01-01
影响因子：
7.3
通讯作者：
WOODRUFF, GN
中科院分区：
文献类型：
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作者：
HORWELL, DC;HUGHES, J;WOODRUFF, GN
本文介绍了神经肽CCK的合成和构效关系(SAR)，从而首次合理地设计了神经肽CCK的“二肽”类似物。化合物[R-(R*，S*)]-4-[[2-[[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[[(tricyclo[3.3.1.1(3，7)]dec-2-yloxy)carbonyl]amino]propyl]amino]-3-phenylpropyl]-amino]-4-oxo-2-butenoic酸(18)，[R-(R*，R*)]-4-[[2-[[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[[(tricyclo[3.3.1.1(3，7)]dec-2-oxy)carbonyl]amino]propyl]amino]-1-phenylethyl]amino]-4-oxo-2-butenoic酸(27)和[R-(R*，R*)]-4-[[2-[[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[[(tricyclo[3.3.1.1(3，7)]dec-2-yloxy)carbonyl]amino]propyl]amino]-1-phenylethyl]amino]-4-oxobutanoic酸(29d)与CCK-B的结合亲和力分别为0.8、0.7和1.7 nm，CCK-A/CCK-B比值分别为550、1100和2500。化合物27在大鼠皮下(Sc)和静脉(Iv)给药均能有效地抑制五肽胃泌素刺激的胃酸分泌，ED50=0.07(0.01-0.34)mU·mol/kg。在黑白试验箱中，化合物29d在0.0001-30 mg/kg sc范围内对小鼠具有抗焦虑作用，其活性与0.125-1 mg/kg ip范围内的安定相当，在本试验中，当口服剂量从0.0001 mg/kg至10 mg/kg时也具有活性。
This paper describes the synthesis and structure-activity relationships (SAR) leading to the first rational design of ''dipeptoid'' analogues of the neuropeptide cholecystokinin (CCK). Compounds [R-(R*,S*)]-4-[[2-[[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[[(tricyclo[3.3.1.1(3,7)]dec-2-yloxy)carbonyl]amino]propyl]amino]-3-phenylpropyl]-amino]-4-oxo-2-butenoic acid (18), [R-(R*,R*)]-4-[[2-[[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[[(tricyclo[3.3.1.1(3,7)]dec-2-oxy)carbonyl]amino]propyl]amino]-1-phenylethyl]amino]-4-oxo-2-butenoic acid (27), and [R-(R*,R*)]-4-[[2-[[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[[(tricyclo[3.3.1.1(3,7)]dec-2-yloxy)carbonyl]amino]propyl]amino]-1-phenylethyl]amino]-4-oxobutanoic acid (29d) have CCK-B binding affinities of IC50 = 0.8, 0.7, and and 1.7 nM with a CCK-A/CCK-B ratio of 550, 1100, and 2500, respectively. Compound 27 is well-absorbed and is equiactive by the subcutaneous (sc) and intravenous (iv) routes of administration in the Ghosh and Schild test in rats in inhibiting pentagastrin stimulated gastric acid secretion with ED50 = 0.07 (0.01-0.34) mu-mol/kg. Compound 29d is anxiolytic in mice in the black-white test box over the range 0.0001-30 mg/kg sc, comparable in activity to diazepam over the range 0.125-1 mg/kg ip), and also active in this test when dosed orally over a wide range from 0.0001 to 10 mg/kg.