CYCLIC MELANOTROPINS .9. 7-D-PHENYLALANINE ANALOGS OF THE ACTIVE-SITE SEQUENCE
CYCLIC MELANOTROPINS .9. 7-D-PHENYLALANINE ANALOGS OF THE ACTIVE-SITE SEQUENCE
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DOI：
10.1021/jm50001a008
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发表时间：
1985-01-01
影响因子：
7.3
通讯作者：
HADLEY, ME
中科院分区：
文献类型：
--
作者：
CODY, WL;MAHONEY, M;HADLEY, ME
环促黑素素。**图形 **。在几种黑素细胞生物测定中确定为高效激动剂。在线性促黑素中，D-Phe 7取代导致增加的效力和通常延长的生物活性。为了确定这种取代是否在环状促黑素中具有相同的效果，制备了一系列这些类似物。D-Phe 7-取代的环状促黑素。图形 **。和 **图形 **。在青蛙或蜥蜴皮肤生物测定中，两者都比它们的含有环状L-Phe 7的对应物更有效超过10倍。在任一测定中，两种肽均未表现出生物活性的延长。D-Phe 7取代成环状4-12和4-13序列导致在两种测定中相对于L-Phe 7对应物的效力轻微增加或没有增加，但是在每种测定中促黑素的活性被超延长。.**图形 **。与之等价 **图形 **。再次证明，与某些含有线性和环状L-Phe 7的促黑素一样，C-末端氨基酸缬氨酸不是生物活性或超效力所必需的。类似于具有超延长促黑素活性的线性D-Phe 7类似物，4-12和4-13环状D-Phe 7类似物也显示出超激动作用的现象，这是与由等效力浓度的天然激素产生的效力相比效力的时间依赖性增加。某些线性促黑素的环化导致类似物对血清酶或纯化的蛋白水解酶的生物降解具有增加的抗性。在环状类似物中掺入D-Phe 7导致对胰蛋白酶的酶失活具有完全抗性的促黑素。
The cyclic melanotropin .**GRAPHIC**. is a highly potent agonist as determined in several melanocyte bioassays. In linear melanotropins, a D-Phe7 substitution leads to increased potency and often prolonged biological activity. In order to determine if this substitution would have the same effect in cyclic melanotropins, a series of these analogs was prepared. The D-Phe7-substituted cyclic melanotropins .**GRAPHIC**. and .**GRAPHIC**. were both more potent than their cyclic L-Phe7-containing counterparts in either the frog or lizard skin bioassay by more than a factor of 10. Neither peptide exhibited prolongation of biological activity in either assay. Substitution of D-Phe7 into the cyclic 4-12 and 4-13 sequences led to a slight or no increase in potency in both assays relative to the L-Phe7 counterparts, but the activity of the melanotropins was ultraprolonged in each assay. .**GRAPHIC**. was about equipotent to .**GRAPHIC**. again demonstrating, as with certain linear and cyclic L-Phe7-containing melanotropins, that the C-terminal amino acid valine is not required for biological activity or for superpotency. Similar to the linear D-Phe7 analogs that possessed ultraprolonged melanotropic activity, the 4-12 and 4-13 cyclic D-Phe7 analogs also displayed the phenomenon of superagonism, which is a time-dependent increase in efficacy over that produced by an equipotent concentration of the native hormone. Cyclization of certain linear melanotropins resulted in analogs with increased resistance to biological degradation by serum enzymes or purified proteolytic enzymes. Incorporation of a D-Phe7 in the cyclic analogs led to melanotropins that were totally resistant to enzymatic inactivation by trypsin.