The pharmacological profile of MEN15596 or (6-methyl-benzo[b]thiophene-2-carboxylic acid [1-(2-phenyl-1R-{[1-(tetrahydropyran-4-ylmethyl)-piperidin-4-ylmethyl]-carbamoyl}-ethylcarbamoyl)-cyclopentyl]-amide), a novel potent and selective tachykinin NK2 receptor antagonist endowed with oral activity, is described. At the human recombinant tachykinin NK2 receptor, MEN15596 showed subnanomolar affinity (pKi 10.1) and potently antagonized (pKB 9.1) the neurokinin A-induced intracellular calcium release. MEN15596 selectivity for the tachykinin NK2 receptor was assessed by binding studies at the recombinant tachykinin NK1 (pKi 6.1) and NK3 (pKi 6.4) receptors, and at a number of 34 molecular targets including receptors, transporters and ion channels. In isolated smooth muscle preparations MEN15596 showed a marked species selectivity at the tachykinin NK2 receptor with the highest antagonist potency in guinea-pig colon, human and pig bladder (pKB 9.3, 9.2 and 8.8, respectively) whereas it was three orders of magnitude less potent in the rat and mouse urinary bladder (pKB 6.3 and 5.8, respectively). In agreement with binding experiments, MEN15596 showed low potency in blocking selective NK1 or NK3 receptor agonist-induced contractions of guinea-pig ileum preparations (pA2

译文

描述了MEN15596或 (6-甲基-苯并 [b]thiophene-2-carboxylic [1-(2-苯基-1r-{[1-(tetrahydropyran-4-ylmethyl)-piperidin-4-ylmethyl]-氨基甲酰基}-乙基氨基甲酰基)-环戊基]-酰胺) 的药理学特征,一种具有口服活性的新型有效和选择性速激肽NK2受体拮抗剂。在人重组速激肽NK2受体上,MEN15596显示亚纳摩尔亲和力 (pKi 10.1),并有效拮抗 (pKB 9.1) 神经激肽A诱导的细胞内钙释放。MEN15596对速激肽NK2受体的选择性通过在重组速激肽NK1 (pKi 6.1) 和NK3 (pKi 6.4) 受体以及在包括受体、转运蛋白和离子通道在内的许多34个分子靶标上的结合研究来评估。在分离的平滑肌制剂中,MEN15596在速激肽NK2受体上显示出明显的物种选择性,在豚鼠结肠,人和猪膀胱中具有最高的拮抗剂效力 (pKB 9.3,9.2和8.8,分别),而在大鼠和小鼠膀胱中效力降低了三个数量级 (分别为pKB 6.3和5.8)。与结合实验一致,MEN15596在阻断选择性NK1或NK3受体激动剂诱导的豚鼠回肠制剂收缩 (pA2 <或 = 6) 方面表现出较低的效力。在麻醉的豚鼠中,MEN15596以剂量相关且持续的方式抑制由选择性速激肽NK2受体激动剂 [betaAla8] 神经激肽a (4-10) (3 nmol/kg静脉注射) 诱导的结肠收缩 (ED50 0.18 micromol/kg),十二指肠内 (ED50 3.16微摩尔/千克) 或口服给药 (10-30微摩尔/千克),不影响NK1受体选择性激动剂 [Sar9] 物质P砜 (3 nmol/千克) 产生的结肠收缩。此外,MEN15596可有效抑制静脉注射引起的支气管收缩。[Βala8] 神经激肽A(4-10) 的给药。总体而言,结果表明MEN15596是一种有效的选择性速激肽NK2受体拮抗剂,对豚鼠,猪和人受体具有高亲和力和效力,在体内实验中作用时间长,口服生物利用度好。

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