We describe the in vitro and in vivo pharmacological properties of MEN 10,627 or cyclo(Met-Asp-Trp-Phe-Dap-Leu)cyclo(2 beta-5 beta), the first example of a polycyclic peptide tachykinin NK2 receptor antagonist. MEN 10,627 is endowed with high affinity for NK2 receptor expressed in various species with pKB values ranging between 10.1 (hamster trachea) and 8.1 (rabbit pulmonary artery). The antagonism is of competitive type in both functional and radioligand binding assays. A 100- to 10,000-fold selectivity was found vs. NK1 or NK3 receptors expressed in various species. As an NK2 receptor antagonist, MEN 10,627 is 10- to 100-fold more potent than the monocyclic peptide antagonist L 659,877 or cyclo(Met-Gln-Trp-Phe-Gly-Leu). At the hamster NK2 receptor, MEN 10,627 is about 30-fold more potent than the nonpeptide NK2 receptor antagonist SR 48,968 [(S)-N-methyl-N[4-acetylamino-4-phenylpiperidino)-2-(3,4-dichlorophenyl) butyl]benzamide], whereas the converse is true for the rabbit NK2 receptor. Furthermore, MEN 10,627 is, up to micromolar concentrations, devoid of antagonist properties toward a wide range of transmitters of both peptide and nonpeptide nature. In urethane-anesthetized rats in vivo, MEN 10,627 (10-100 nmol/kg i.v.) produced long-lasting inhibition of contraction of the urinary bladder and duodenum produced by i.v. administration of the NK2 receptor agonist [beta Ala8]NKA(4-10), without affecting the responses produced by i.v. administration of the NK1 receptor agonist [Sar9]SP sulfone or acetylcholine. In anesthetized rats, both MEN 10,627 and SR 48,968 blocked urinary bladder contraction induced by the NK2 receptor agonist after intravenous, intranasal or intraduodenal administration. Equieffective doses of MEN 10,627 producing about 50% inhibition of the response to [beta Ala8]NKA(4-10) in the rat urinary bladder in vivo, were 0.01, 0.03 and 3 mumol/kg after intravenous, intranasal and intraduodenal administration, respectively. The corresponding doses of SR 48,968 were 0.03, 0.1 and 1 mumol/kg, after intravenous, intranasal and intraduodenal administration, respectively. In conclusion, MEN 10,627 is a potent and selective NK2 receptor antagonist, endowed with high potency and long duration of action in vivo, which is not restricted to parenteral administration.(ABSTRACT TRUNCATED AT 400 WORDS)

中文翻译：

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MEN 10,627，速激肽NK2受体的新型多环肽拮抗剂。

我们描述了MEN 10,627或环（Met-Asp-Trp-Phe-Dap-Leu）cyclo（2 beta-5 beta）（多环肽速激肽NK2受体拮抗剂的第一个实例）的体外和体内药理特性。MEN 10,627对在各种物种中表达的NK2受体具有高度亲和力，pKB值介于10.1（仓鼠气管）和8.1（兔子肺动脉）之间。在功能和放射性配体结合测定中，拮抗作用都是竞争性的。与在各种物种中表达的NK1或NK3受体相比，发现其选择性高出100到10,000倍。作为NK2受体拮抗剂，MEN 10,627的效力比单环肽拮抗剂L 659,877或环（Met-Gln-Trp-Phe-Gly-Leu）高10至100倍。在仓鼠NK2受体上，MEN 10,627的功效比非肽NK2受体拮抗剂SR 48高约30倍，968 [（S）-N-甲基-N [4-乙酰氨基-4-苯基哌啶子基-2-（3,4-二氯苯基）丁基]苯甲酰胺]，而对于兔NK2受体则相反。此外，MEN 10,627的浓度不超过微摩尔浓度，对多种肽和非肽性质的递质都没有拮抗作用。在体内经尿烷麻醉的大鼠中，MEN 10,627（10-100 nmol / kg iv）对静脉注射NK2受体激动剂[beta Ala8] NKA（4-10）产生的膀胱和十二指肠收缩产生长期抑制作用），而不会影响通过静脉注射NK1受体激动剂[Sar9] SP砜或乙酰胆碱产生的应答。在麻醉的大鼠中，MEN 10,627和SR 48,968均阻断了NK2受体激动剂静脉注射后引起的膀胱收缩，鼻内或十二指肠内给药。静脉内，鼻内和十二指肠内给药后，在大鼠膀胱体内，产生约50％抑制对βAla8] NKA（4-10）反应的MEN 10,627的等效剂量分别为0.01、0.03和3 mumol / kg。 。静脉内，鼻内和十二指肠内给药后，SR 48,968的相应剂量分别为0.03、0.1和1 mumol / kg。综上所述，MEN 10,627是一种有效且选择性的NK2受体拮抗剂，在体内具有高效力和长效作用，并且不限于肠胃外给药。（摘要截短为400字）静脉内，鼻内和十二指肠内给药后分别为03和3 mumol / kg。静脉内，鼻内和十二指肠内给药后，SR 48,968的相应剂量分别为0.03、0.1和1 mumol / kg。总之，MEN 10,627是一种有效且选择性的NK2受体拮抗剂，在体内具有高效力和长效作用，而不仅限于肠胃外给药。（摘要截短为400字）静脉内，鼻内和十二指肠内给药后分别为03和3 mumol / kg。静脉内，鼻内和十二指肠内给药后，SR 48,968的相应剂量分别为0.03、0.1和1 mumol / kg。综上所述，MEN 10,627是一种有效且选择性的NK2受体拮抗剂，在体内具有高效力和长效作用，并且不限于肠胃外给药。（摘要截短为400字）