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首页> 外文期刊>Canadian Journal of Physiology and Pharmacology >Potent and selective tools to investigate neuropeptide Y receptors in the central and peripheral nervous systems: BIB03304 (Y1) and CGP71683A (Y5).
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Potent and selective tools to investigate neuropeptide Y receptors in the central and peripheral nervous systems: BIB03304 (Y1) and CGP71683A (Y5).

机译：研究中枢神经系统和周围神经系统中神经肽Y受体的有力和选择性工具：BIB03304（Y1）和CGP71683A（Y5）。

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摘要

We have evaluated 3 newly developed neuropeptide Y receptor antagonists in various in vitro binding and bioassays: BIBO3304 (Y1), T4[NPY33-36]4 (Y2), and CGP71683A (Y5). In rat brain homogenates, BIBO3304 competes for the same population of [125I][Leu31,Pro34] peptide YY (PYY) binding sites (75%) as BIBP3226, but with a 10 fold greater affinity (IC50 of 0.2 +/- 0.04 nM for BIBO3304 vs. 2.4 +/- 0.07 nM for BIBP3226),while CGP71683A has high affinity for 25% of specific [125I][Leu31,Pro34]PYY binding sites. Both BIBO3304 and CGP71683A (at 1.0 microM) were unable to compete for a significant proportion of specific [125I]PYY3-36/Y2 sites. The purported Y2 antagonist T4[NPY33-36]4 competed against [125I]PYY3-36 binding sites with an affinity of 750 nM. These results were confirmed in HEK 293 cells transfected with either the rat Y1, Y2, Y4, or Y5 receptor cDNA. BIBO3304, but not CGP71683A, competed with high affinity for [125I][Leu31,Pro34]PYY binding sites in HEK 293 cells transfected with the rat Y1 receptor cDNA, whereas the reverse profile was observed upon transfection with the rat Y5 receptor cDNA. Additionally, both molecules were inactive at Y2 and Y4 receptor subtypes expressed in HEK 293 cells. Receptor autoradiographic studies revealed the presence of [125I][Leu31,Pro34]PYY/BIBO3304-insensitive sites in the rat brain as reported previously for BIBP3226. Finally, the selective antagonistic properties of BIBO3304 were demonstrated in a Y1 bioassay (rabbit saphenous vein; pA2 value of 9.04) while being inactive in Y2 (rat vas deferens) and Y4 (rat colon) bioassays. These results confirm the high affinity and selectivity of BIBO3304 and CGP71683A for the Y1 and Y5 receptor subtypes, respectively, while the purported Y2 antagonist, T4[NPY33-36]4 possesses rather low affinity for this receptor.
机译：我们在各种体外结合和生物测定中评估了3种新开发的神经肽Y受体拮抗剂：BIBO3304（Y1），T4 [NPY33-36] 4（Y2）和CGP71683A（Y5）。在大鼠脑匀浆中，BIBO3304与BIBP3226竞争相同的[125I] [Leu31，Pro34] YY肽YY（PYY）结合位点群体（75％），但亲和力高10倍（IC50为0.2 +/- 0.04 nM （对于BIBO3304，则为2.4 +/- 0.07 nM，对于BIBP3226，则为2.4 +/- 0.07 nM），而CGP71683A对25％的特定[125I] [Leu31，Pro34] PYY结合位点具有高亲和力。 BIBO3304和CGP71683A（1.0 microM）都无法竞争很大比例的特定[125I] PYY3-36 / Y2特定位点。声称的Y2拮抗剂T4 [NPY33-36] 4与[125I] PYY3-36结合位点竞争，亲和力为750 nM。在用大鼠Y1，Y2，Y4或Y5受体cDNA转染的HEK 293细胞中证实了这些结果。 BIBO3304，而不是CGP71683A，以高亲和力竞争转染大鼠Y1受体cDNA的HEK 293细胞中的[125I] [Leu31，Pro34] PYY结合位点，而转染大鼠Y5受体cDNA时观察到相反的情况。另外，两个分子在HEK 293细胞中表达的Y2和Y4受体亚型上均无活性。受体放射自显影研究表明，如先前针对BIBP3226的报道，大鼠脑中存在[125I] [Leu31，Pro34] PYY / BIBO3304-不敏感位点。最后，在Y1生物测定（兔隐静脉; pA2值为9.04）中证明了BIBO3304的选择性拮抗特性，而在Y2（大鼠输精管）和Y4（大鼠结肠）生物测定中不起作用。这些结果证实了BIBO3304和CGP71683A分别对Y1和Y5受体亚型具有高亲和力和选择性，而据称Y2拮抗剂T4 [NPY33-36] 4对该受体具有相当低的亲和力。

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