Cholecystokinin dipeptoid antagonists: design, synthesis, and anxiolytic profile of some novel CCK-A and CCK-B selective and "mixed" CCK-A/CCK-B antagonists.
Cholecystokinin dipeptoid antagonists: design, synthesis, and anxiolytic profile of some novel CCK-A and CCK-B selective and "mixed" CCK-A/CCK-B antagonists.
复制标题
胆囊收缩素二肽拮抗剂：一些新型 CCK-A 和 CCK-B 选择性和“混合”CCK-A/CCK-B 拮抗剂的设计、合成和抗焦虑特性。
DOI：
10.1021/jm00057a005
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发表时间：
1993
影响因子：
7.3
通讯作者：
G. N. Woodruff
中科院分区：
文献类型：
--
作者：
P. Boden;M. Higginbottom;D. R. Hill;D. Horwell;John Hughes;David C. Rees;E. Roberts;L. Singh;N. Suman;G. N. Woodruff
设计，合成，和结构-活性关系（SAR）的开发选择性二肽类配体的胆囊收缩素（CCK）受体亚型CCK-A和CCK-B的描述。开发的SAR用于设计对CCK-A和CCK-B受体具有相等纳摩尔结合亲和力的配体。实例化合物如[1 R-[1 α [R*（R*）]，2 β]]-4-[[2-[[3-[[4-（4-甲基吡啶-2-基）-2-基）氨基]苯基]-2-氧代-3-甲基吡啶-2-基]苯基]氨基甲酸酯。（1H-吲哚-3-基）-2-甲基-2-[（2-甲基环己基）氧基]羰基]氨基]-1-氧代丙基]-氨基]-1-苯乙基]氨基]-4-氧代-丁酸（24 c），（1 R-反式）-N-[α-甲基-N-[[（2-甲基环己基）氧基]羰基]-D-异丙基]-L-3-（苯基甲基）-β-丙氨酸（28 i），和N-[α-甲基-N-[（三环[3.3.1.1]癸-2-基氧基）羰基]-D-异丙基]-L-3-（苯基甲基）-β-丙氨酸（28 i），（苯甲基）-β-丙氨酸（30 m）是CCK-B选择性化合物，其CCK-B结合亲和力的IC 50分别为3.9、0.34和0.15 nM，CCK-A/CCK-B比值分别为464、53和170。其它化合物如（1 R-反式）-N-[α-甲基-N-[[（2-甲基环己基）氧基]羰基]-L-叔丁基]-D-3-（苯基甲基）-β-丙氨酸（281）和N-（α-甲基-N-[（三环[3.3.1.1]癸-2-基氧基）羰基]-L -叔丁基]-D-3-（苯基甲基）-β-丙氨酸（281）。（苯甲基）-β-丙氨酸（30 p）是CCK-A选择性化合物，其CCK-A结合亲和力的IC 50 = 7.9和2.82 nM，CCK-A/CCK-B比率为0.007和0.01，分别此外，（1 S-反式）-N-[α-甲基-N-[[（2-甲基环己基）氧基]羰基]-D-甲基]-L-3-（苯甲基）-β-丙氨酸（28 h）是一种混合的CCK-A/CCK-B配体，其CCK-A结合亲和力为IC 50 = 3.9 nM，CCK-B结合亲和力为IC 50 = 4.2，产生CCK-A/CCK-B比值为1。在大鼠下丘脑腹内侧核的电生理试验中，CCK-B选择性化合物显示为拮抗剂，平衡常数（Ke）值为2.8nM，持续30个月;在小鼠光/暗箱试验中，CCK-B选择性化合物也显示为抗焦虑剂，最小有效剂量为0.01mg/kg，sc，持续30个月。CCK-A选择性化合物也被证明是竞争性拮抗剂，通过抑制CCK-8 S诱导的胰腺腺泡细胞淀粉酶分泌，30 μ g的Ke值为16 nM。在大鼠背中缝（一个富含CCK-A受体的区域）的电生理测试中，30 p的Ke值为12.8 nM。混合CCK-A/CCK-B化合物28 h在CCK-A和CCK-B模型中均显示拮抗性质;因此，它抑制CCK-8 S诱导的胰腺腺泡细胞淀粉酶分泌，并且在光/暗箱范例中具有抗焦虑作用。（400字处截断摘要）
The design, synthesis, and structure-activity relationships (SAR) for the development of selective dipeptoid ligands for both of the cholecystokinin (CCK) receptor subtypes CCK-A and CCK-B are described. The SAR developed is used to design a ligand with equal nanomolar binding affinity for both the CCK-A and CCK-B receptors. Example compounds such as [1R-[1 alpha[R*(R*)],2 beta]]-4-[[2-[[3-(1H-indol-3-yl)- 2-methyl-2-[[[(2-methylcyclohexyl)oxy]carbonyl]amino]-1- oxopropyl]-amino]-1-phenylethyl]amino]-4-oxo-butanoic acid (24c), (1R-trans)-N-[alpha-methyl-N-[[(2-methylcyclohexyl)oxy] carbonyl]-D-tryptophyl]-L-3-(phenylmethyl)-beta-alanine (28i), and N-[alpha-methyl-N-[(tricyclo[3.3.1.1]dec-2-yloxy) carbonyl]-D-tryptophanyl]-L-3-(phenylmethyl)-beta-alanine (30m) are CCK-B selective compounds having CCK-B binding affinities of IC50 = 3.9, 0.34, and 0.15 nM with a CCK-A/CCK-B ratio of 464, 53, and 170, respectively. Other compounds such as (1R-trans)-N-[alpha-methyl-N-[[(2-methylcyclohexyl)oxy]carbonyl]- L-tryptophyl]-D-3-(phenylmethyl)-beta-alanine (281) and N-(alpha-methyl-N-[(tricyclo[3.3.1.1]dec-2-yloxy)carbonyl]-L - tryptophyl]-D-3-(phenylmethyl)-beta-alanine (30p) are CCK-A-selective compounds having CCK-A binding affinities of IC50 = 7.9 and 2.82 nM with a CCK-A/CCK-B ratio of 0.007 and 0.01, respectively. Further to these, (1S-trans)-N-[alpha-methyl-N-[[(2-methylcyclohexyl)oxy] carbonyl]-D-tryptophyl]-L-3-(phenylmethyl)-beta-alanine (28h) is a mixed CCK-A/CCK-B ligand with a CCK-A binding affinity of IC50 = 3.9 nM and a CCK-B binding affinity of IC50 = 4.2, producing a CCK-A/CCK-B ratio of unity. The CCK-B selective compounds are shown to be antagonists in electrophysiological tests on the rat ventromedial nucleus of the hypothalamus with an equilibrium constant (Ke) value of 2.8 nM for 30m and are also shown to be anxiolytic in the mouse ligh/dark box test with a minimum effective dose of 0.01 mg/kg, sc, for 30m. The CCK-A selective compounds are also shown to be competitive antagonists by the inhibition of CCK-8S-evoked amylase secretion from pancreatic acinar cells with a Ke value of 16 nM for 30p. In electrophysiological tests on the rat dorsal raphé (an area rich in CCK-A receptors) 30p had a Ke value of 12.8 nM. The mixed CCK-A/CCK-B compound 28h showed antagonistic properties in both CCK-A and CCK-B models; thus it inhibited CCK-8S-evoked amylase secretion from pancreatic acinar cells and is anxiolytic in the light/dark box paradigm.(ABSTRACT TRUNCATED AT 400 WORDS)