POTENT AND PROLONGED ACTING CYCLIC LACTAM ANALOGS OF ALPHA-MELANOTROPIN - DESIGN BASED ON MOLECULAR-DYNAMICS
POTENT AND PROLONGED ACTING CYCLIC LACTAM ANALOGS OF ALPHA-MELANOTROPIN - DESIGN BASED ON MOLECULAR-DYNAMICS
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DOI：
10.1021/jm00132a010
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发表时间：
1989-12-01
影响因子：
7.3
通讯作者：
HRUBY, VJ
中科院分区：
文献类型：
--
作者：
ALOBEIDI, F;CASTRUCCI, AMD;HRUBY, VJ
利用以往的构效关系和理论研究的结果。-melanotropin (.alpha。- msh, Ac- ser - tyrr - ser - met - glu - his - phe - arg - trp - gly - lys - pro - val - nh2)及其相关的超强类似物Ac-[Nle4，d-Phe7]-.alpha。- msh和Ac-[Cys4，Cys10]-.alpha。-MSH，我们设计了一个新的类。-MSH4-13和。alpha。-MSH4-10环内酰胺片段- α -促黑素类似物。环状肽具有以下一般结构：Ac-[Nel4，Xxx5,D-Phe7, Yyy10Gly11]-.alpha。-MSH4-13-NH2和Ac[Nle4，Xxx5,D-Phe7,Yyy10]-.alpha。-MSH4-10-NH2，其中Xxx = Glu或Asp， Yyy = Lys, Orn， Dab或Dpr。侧链基团Xxx和Yyy之间的内酰胺桥的形成可以在溶液中进行，也可以在固相载体上进行。制备了7种环肽，并采用标准蛙（Rana pipiens）和蜥蜴（Anolis carolinensis）皮肤生物测定法对其促黑活性进行了生物测定。相对于。-MSH（相对效价= 1），环肽在蜥蜴皮肤生物测定中的效价如下：-MSH (1);Ac - [Nle4 Glu5、D-Phe7 Lys10, Gly11] -.alpha。-MSH4-13-NH2 (6);Ac - [Nle4 Asp5、D-Phe7 Lys10, Gly11] -.alpha。-MSH4-13-NH2 (100);Ac - [Nle4 Glu5、D-Phe7 Lys10] -.alpha。-MSH4-10-NH2 (9);Ac - [Nle4 Asp5、D-Phe7 Lys10] -.alpha。-MSH4-10-NH2 (90);Ac - [Nle4 Asp5、D-Phe7 Orn10] -.alpha。-MSH4-10-NH2 (20);Ac - [Nle4 Asp5、D-Phe7 Dab10] -.alpha。-MSH4-10-NH2 (5);Ac - [Nel4 Asp5、D-Phe7 Dpr10] -.alpha。-MSH4-10-NH2(5)。在青蛙皮肤生物测定中也得到了类似的结果，但类似物的效力要小得多。具有23元环的环状促黑素的促黑力是. α的100倍。-MSH对蜥蜴黑素细胞受体的选择性优于青蛙黑素细胞受体。从23增加或减少这些环状促黑素的环大小会降低所产生的环状肽的生物效力。23元和24元环类似物在两种生物分析中都显示出持久的（残余的）生物活性，但较小的环系统（20,21,22）没有。这些结果为α的结构和构象要求提供了新的见解。-MSH及其类似物作用于两种不同类型的色素细胞（黑素细胞）受体。
Utilizing results from previous structure-activity relationships and theoretical studies of .alpha.-melanotropin (.alpha.-MSH, Ac-Ser-Tyr-Ser-Met-Glu-His-Phe-Arg-Trp-Gly-Lys-Pro-Val-NH2) and its related superpotent analogues, Ac-[Nle4,d-Phe7]-.alpha.-MSH and Ac-[Cys4,Cys10]-.alpha.-MSH, we have designed a new class of .alpha.-MSH4-13 and .alpha.-MSH4-10 cyclic lactam fragment analogues of .alpha.-melanotropin. The cyclic peptides have the following general structures: Ac-[Nel4,Xxx5,D-Phe7, Yyy10Gly11]-.alpha.-MSH4-13-NH2 and Ac[Nle4,Xxx5,D-Phe7,Yyy10]-.alpha.-MSH4-10-NH2, where Xxx = Glu or Asp and Yyy = Lys, Orn, Dab, or Dpr. Formation of the lactam bridge between the side-chain groups Xxx and Yyy was performed either in solution or on a solid-phase support. Seven cyclic peptides were prepared and bioassayed for their melanotropic potency by using standard frog (Rana pipiens) and lizard (Anolis carolinensis) skin bioassays. Relative to .alpha.-MSH (relative potency = 1), the potencies of the cyclic peptides in the lizard skin bioassay were as follows: .alpha.-MSH (1); Ac-[Nle4,Glu5,D-Phe7,Lys10,Gly11]-.alpha.-MSH4-13-NH2 (6); Ac-[Nle4,Asp5,D-Phe7,Lys10,Gly11]-.alpha.-MSH4-13-NH2 (100); Ac-[Nle4,Glu5,D-Phe7,Lys10]-.alpha.-MSH4-10-NH2 (9); Ac-[Nle4,Asp5,D-Phe7,Lys10]-.alpha.-MSH4-10-NH2 (90); Ac-[Nle4,Asp5,D-Phe7,Orn10]-.alpha.-MSH4-10-NH2 (20); Ac-[Nle4,Asp5,D-Phe7,Dab10]-.alpha.-MSH4-10-NH2 (5); Ac-[Nel4,Asp5,D-Phe7,Dpr10]-.alpha.-MSH4-10-NH2 (5). Similar results were obtained in the frog skin bioassay, but the analogues were much less potent. Cyclic melanotropins with 23-membered rings exhibited 100-fold higher malanotropic potency than .alpha.-MSH with selectivity for the lizard melanocyte receptors over the frog melanocyte receptors. Increasing or decreasing the ring size of these cyclic melanotropins from 23 diminishes the biological potency of the resulting cyclic peptide. The 23- and 24-membered ring analogues showed prolonged (residual) biological activities in both biological assays, but the smaller ring systems (20, 21, 22) did not. These results provide new insights into the structural and conformational requirements of .alpha.-MSH and its analogues at two different types of pigment cell (melanocyte) receptors.