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
：MEN15596或（6-甲基-苯并[b]噻吩-2-羧酸[1-（2-苯基-1R-{[1-（四氢吡喃-4-基甲基）-哌啶-4-基甲基]描述了一种具有口服活性的新型有效且选择性的速激肽NK2受体拮抗剂-（氨基甲酰基}-乙基氨基甲酰基）-环戊基]-酰胺）。在人类重组速激肽NK2受体上，MEN15596显示出纳摩尔亲和力（pKi 10.1），并强烈拮抗（pKB 9.1）神经激肽A诱导的细胞内钙释放。通过在重组速激肽NK1（pKi 6.1）和NK3（pKi 6.4）受体以及包括受体，转运蛋白和离子通道在内的34个分子靶标上的结合研究评估了MEN15596对速激肽NK2受体的选择性。在分离的平滑肌制剂中，MEN15596在速激肽NK2受体上具有明显的物种选择性，在豚鼠结肠，人和猪膀胱中的拮抗效力最高（分别为pKB 9.3、9.2和8.8），而效力却低了三个数量级。在大鼠和小鼠的膀胱中（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的收缩中表现出较低的效力（pA2 <或= 6）。在麻醉的豚鼠中，MEN15596以剂量相关和持续的方式抑制选择性速激肽NK2受体激动剂[βAla8]神经激肽A（4-10）（3 nmol / kg iv）诱导的结肠收缩，无论是静脉注射（ED50） 0.18 micromol / kg），十二指肠内（ED50 3.16 micromol / kg）或口服（10-30 micromol / kg），以3 micromol / kg静脉注射时，不会影响NK1受体选择性激动剂[Sar9]物质产生的结肠收缩对砜（3nmol / kg iv）。另外，MEN15596可有效抑制静脉内注射产生的支气管收缩。 βAla8]神经激肽A（4-10）的给药。总体而言，结果表明MEN15596是一种有效且选择性的速激肽NK2受体拮抗剂，对豚鼠，猪和人的受体具有高亲和力和效力，在体内实验中作用时间长，并且口服生物利用度良好。
