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LF 16.0335, a novel potent and selective nonpeptide antagonist of the human bradykinin B2 receptor

机译：LF 16.0335，人类缓激肽B2受体的新型有效选择性非肽拮抗剂

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In the present paper, we describe the in vitro pharmacological properties of LF 16.0335 (1-[[3-[(2,4-dimethylquinolin-8-yl)oxymethyl]-2,4-dichloro-phenyl]sulphonyl] -2(S) - [[4 -[4-(aminoiminomethyl)phenylcarbonyl]piperazin-1-yl]carbonyl]pyrrolidine), a novel and potent nonpeptide antagonist of the human bradykinin (BK) B2 receptor.LF 16.0335 displaced [3H]-BK binding to membrane preparations from CHO cells expressing the cloned human B2 receptor, INT 407 cells and human umbilical vein with Ki values of 0.84±0.39 nM, 1.26±0.68 nM and 2.34±0.36 nM, respectively.In saturation binding studies performed in INT 407 cell membranes in the presence or absence of LF 16.0335, Bmax values of [3H]-BK were not significantly changed suggesting that LF 16.0335 behaves as a competitive antagonist.LF 16.0335 had no affinity for the cloned human kinin B1 receptor stably expressed in 293 cells. In addition, this compound at 1 μM did not significantly bind to a range of 40 different membrane receptors and eight ion channels except muscarinic M2 and M1 receptors for which an IC50 value of 0.9 and 1 μM was obtained.BK stimulates in a concentration-dependent manner phosphoinositosides (IPs) production in cultured INT 407 cells. Concentration-response-curves to BK were shifted to the right in the presence of LF 16.0335 (0.1 μM) without reduction of the maximum. LF 16.0335 inhibited the concentration-contraction curve to BK in the human umbilical vein giving a pA2 value of 8.30±0.30 with a Schild plot slope that was not different from unity.These results demonstrate that LF 16.0335 is a potent, selective and competitive antagonist of the human bradykinin B2 receptor.
机译：在本文中，我们描述了LF 16.0335（1-[[[3-[（2,4-二甲基喹啉-8-基）氧甲基] -2,4-二氯-苯基]磺酰基] -2（ S）-[[[4-[4-（氨基亚氨基甲基）苯基羰基]哌嗪-1-基]羰基]吡咯烷），一种新型有效的人缓激肽（BK）B2受体非肽拮抗剂。LF16.0335取代[3H] -BK与表达克隆的人B2受体的CHO细胞膜制剂，INT 407细胞和人脐静脉的膜制剂结合，Ki值分别为0.84±0.39 nM，1.26±0.68 nM和2.34±0.36 nM。在INT 407中进行的饱和结合研究在存在或不存在LF 16.0335的情况下，细胞膜的[3H] -BK的Bmax值没有显着变化，表明LF 16.0335充当竞争性拮抗剂。LF16.0335对在293细胞中稳定表达的克隆的人激肽B1受体没有亲和力。此外，除了毒蕈碱M2和M1受体的IC50值分别为0.9和1μM之外，这种浓度为1μM的化合物没有明显结合40种不同的膜受体和8个离子通道.BK以浓度依赖性刺激在培养的INT 407细胞中磷酸肌醇苷（IPs）的生产方法。在存在LF 16.0335（0.1μM）的情况下，对BK的浓度响应曲线向右移动，而最大值没有降低。 LF 16.0335抑制人脐静脉中BK的浓度-收缩曲线，pA2值为8.30±0.30，Schild图斜率与单位无异。这些结果表明LF 16.0335是一种有效的，选择性的和竞争性的拮抗剂人类缓激肽B2受体。

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