Quartara L, Pavone V, Pedone C, Lombardi A, Renzetti A R, Maggi C A
Chemistry Research Department, A. Menarini Industrie Farmaceutiche Riunite, Firenze, Italy.
Regul Pept. 1996 Aug 27;65(1):55-9. doi: 10.1016/0167-0115(96)00072-9.
We review the reported data on the design, the conformational features and the pharmacological properties of the bicyclic peptide tachykinin NK2 receptor antagonist MEN 10,627 or cyclo(Met-Asp-Trp-Phe-Dap-Leu)cyclo(2 beta-5 beta). MEN 10,627 possesses a highly constrained structure characterized by two consecutive beta-turns, as confirmed by the almost coincident results of NMR and X-ray analyses. The compound has been efficiently synthesized by solid-phase methodology using either Boc or Fmoc strategies. It is quite stable to metabolic degradation and is endowed with high affinity and selectivity for NK2 receptor expressed in various species. At the hamster NK2 receptor MEN 10,627 is about 30-fold more potent than the nonpeptide NK2 receptor antagonist, SR 48,968, while the converse is true for the rabbit NK2 receptor. MEN 10,627 and SR 48,968 show comparable affinities for the human NK2 receptor. MEN 10,627 produces a long lasting inhibition of the response to the selective NK2 receptor agonist [beta Ala8]NKA(4-10) in the rat urinary bladder in vivo after intravenous, intranasal and intraduodenal administration. Therefore different administration routes are possible for this compound that overcomes the usual drawbacks for the application of peptides as drugs.
我们综述了有关双环肽速激肽NK2受体拮抗剂MEN 10,627或环（甲硫氨酸-天冬氨酸-色氨酸-苯丙氨酸-二氨基丙酸-亮氨酸）环（2β-5β）的设计、构象特征和药理特性的报道数据。MEN 10,627具有高度受限的结构，其特征为两个连续的β-转角，NMR和X射线分析结果几乎一致证实了这一点。该化合物已通过使用Boc或Fmoc策略的固相方法高效合成。它对代谢降解相当稳定，对在各种物种中表达的NK2受体具有高亲和力和选择性。在仓鼠NK2受体上，MEN 10,627的效力比非肽类NK2受体拮抗剂SR 48,968高约30倍，而在兔NK2受体上情况则相反。MEN 10,627和SR 48,968对人NK2受体显示出相当的亲和力。静脉内、鼻内和十二指肠内给药后，MEN 10,627在体内对大鼠膀胱中选择性NK2受体激动剂[β丙氨酸8]NKA(4-10)的反应产生持久抑制。因此，该化合物有不同的给药途径，克服了肽类作为药物应用时通常存在的缺点。
