Gastrin-Releasing Peptide/Neuromedin B Receptor Antagonists PD176252, PD168368, and Related Analogs Are Potent Agonists of Human Formyl-Peptide Receptors
Gastrin-Releasing Peptide/Neuromedin B Receptor Antagonists PD176252, PD168368, and Related Analogs Are Potent Agonists of Human Formyl-Peptide Receptors
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DOI：
10.1124/mol.110.068288
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发表时间：
2011-01-01
影响因子：
3.6
通讯作者：
Quinn, Mark T.
中科院分区：
文献类型：
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作者：
Schepetkin, Igor A.;Kirpotina, Liliya N.;Quinn, Mark T.
N-甲酰基肽受体（FPR）是G蛋白偶联受体（GPCR），参与宿主防御和感知细胞功能障碍。因此，FPR代表重要的治疗靶标。在本研究中，我们筛选了32个无关GPCR的配体（激动剂和拮抗剂），以确定其诱导人中性粒细胞和转染人FPR 1、FPR 2或FPR 3的HL-60细胞中细胞内Ca 2+动员的能力。这些化合物的筛选表明，胃泌素释放肽/神经介肽B受体（BB 1/BB 2）的拮抗剂PD 168368 [（S）-α-甲基-α-[（4-硝基苯基）氨基]羰基]氨基]-N-[[1-（2-吡啶基）环己基]甲基]-1H-吲哚-3-丙酰胺]和PD 176252 [（S）-N-[[1-（2-吡啶基）环己基]甲基]-1H-吲哚-3-丙酰胺]。（5-甲氧基-2-吡啶基）环己基]甲基]-α-甲基-α-[[-（4-硝基苯基）氨基]羰基]氨基-1H-吲哚-3-丙酰胺]是有效的混合FPR 1/FPR 2激动剂，具有纳摩尔EC 50值。胆囊收缩素-1受体激动剂A-71623 [Boc-Trp-Lys（epsilon-N-2-methylphenylaminocarbonyl）-Asp-（N-methyl）-Phe-NH 2]也是一种混合的FPR 1/FPR 2激动剂，但具有微摩尔EC 50。筛选56 Trp和Phe为基础的PD 176252/PD 168368类似物和41相关的非肽/非类肽类似物，发现22个额外的FPR激动剂。大多数是有效的混合FPR 1/FPR 2/FPR 3激动剂，FPR 2的EC 50值为纳摩尔，使其成为迄今为止报道的最有效的非肽FPR 2激动剂之一。此外，这些激动剂也是鼠和人中性粒细胞的强效化学引诱剂，并激活人中性粒细胞中的活性氧产生。使用场点方法的选定的激动剂的分子建模，使我们能够修改我们以前报道的FPR 2配体结合位点的药效团模型。该模型表明，存在三个疏水/芳香亚口袋和几个FPR 2激动剂在该受体的跨膜区的结合姿势。这些研究表明，FPR激动剂可能包括不相关的GPCR的配体，并且对这些化合物的分析可以增强我们对这些配体的药理学作用的理解。
N-Formyl peptide receptors (FPRs) are G protein-coupled receptors (GPCRs) involved in host defense and sensing cellular dysfunction. Thus, FPRs represent important therapeutic targets. In the present studies, we screened 32 ligands (agonists and antagonists) of unrelated GPCRs for their ability to induce intracellular Ca2+ mobilization in human neutrophils and HL-60 cells transfected with human FPR1, FPR2, or FPR3. Screening of these compounds demonstrated that antagonists of gastrin-releasing peptide/neuromedin B receptors (BB1/BB2) PD168368 [(S)-a-methyl-a-[[[(4-nitrophenyl)amino]carbonyl]amino]-N-[[1-(2-pyridinyl) cyclohexyl] methyl]-1H-indole-3-propanamide] and PD176252 [(S)-N-[[1-(5-methoxy-2-pyridinyl)cyclohexyl]methyl]-a-methyl-a-[[-(4-nitrophenyl)amino]carbonyl]amino-1H-indole-3-propanamide] were potent mixed FPR1/FPR2 agonists, with nanomolar EC50 values. Cholecystokinin-1 receptor agonist A-71623 [Boc-Trp-Lys(epsilon-N-2-methylphenylaminocarbonyl)-Asp-(N-methyl)-Phe-NH2] was also a mixed FPR1/FPR2 agonist, but with a micromolar EC50. Screening of 56 Trp- and Phe-based PD176252/PD168368 analogs and 41 related nonpeptide/nonpeptoid analogs revealed 22 additional FPR agonists. Most were potent mixed FPR1/FPR2/FPR3 agonists with nanomolar EC50 values for FPR2, making them among the most potent nonpeptide FPR2 agonists reported to date. In addition, these agonists were also potent chemoattractants for murine and human neutrophils and activated reactive oxygen species production in human neutrophils. Molecular modeling of the selected agonists using field point methods allowed us to modify our previously reported pharmacophore model for the FPR2 ligand binding site. This model suggests the existence of three hydrophobic/aromatic subpockets and several binding poses of FPR2 agonists in the transmembrane region of this receptor. These studies demonstrate that FPR agonists could include ligands of unrelated GPCR and that analysis of such compounds can enhance our understanding of pharmacological effects of these ligands.