Davey A E, Horwell D C
Parke-Davis Neurosciences Research Centre, Addenbrooke's Hospital Site, Cambridge, U.K.
Bioorg Med Chem. 1993 Jul;1(1):45-58. doi: 10.1016/s0968-0896(00)82102-1.
This paper describes the use of the non-peptidal N-(2-adamantyloxycarbonyl)-alpha-methyl tryptophan phenylethylamide template of the "peptoid" CCK B antagonist compounds 1 as a basis to probe the functional group requirements of the CCK B receptor in order to produce an agonist response. Comparison of the peptoid template with inter-group distances in a fully extended conformation of the endogenous CCK-B agonist CCK 30-33 led to the design of a series of compounds 2 containing additional Ph, COOH and CONH2, functions at distances from the Trp indole ring that are able to mimic those in the natural ligand. The effect of these modifications was then assessed by measurement of CCK B binding affinities and potential agonist efficacy was investigated by comparison with contraction of guinea-pig isolated stomach corpus muscle strip stimulated by the CCK-B agonist pentagastrin. All compounds showed sub-micromolar binding affinities with each series displaying discernible dependence on intermediate chain length. All compounds (except 2f) were shown to be good CCK B antagonists; no compounds showed significant agonist activity up to a concentration of 1 microM.
本文描述了使用“类肽”CCK B拮抗剂化合物1的非肽类N-(2-金刚烷氧基羰基)-α-甲基色氨酸苯乙酰胺模板作为基础，来探究CCK B受体的官能团需求，以产生激动剂反应。将类肽模板与内源性CCK-B激动剂CCK 30-33完全伸展构象中的基团间距离进行比较，从而设计出一系列化合物2，这些化合物在距色氨酸吲哚环一定距离处含有额外的苯基、羧基和氨基甲酰基官能团，能够模拟天然配体中的相应官能团。然后通过测量CCK B结合亲和力来评估这些修饰的效果，并通过与CCK-B激动剂五肽胃泌素刺激的豚鼠离体胃体肌条收缩情况进行比较，来研究潜在的激动剂效力。所有化合物均表现出亚微摩尔级的结合亲和力，且每个系列对中间链长度都有明显的依赖性。所有化合物（除2f外）均显示为良好的CCK B拮抗剂；在浓度高达1 microM时，没有化合物表现出显著的激动剂活性。
