八肽胆囊收缩素的结构与活性关系

本文采用液相多肽合成法制备了八肽胆囊收缩素(CCK_8)的六种类似物,并测定了它们诱导离体的豚鼠胆囊收缩的生物学活性。发现CCK_8的N-端乙酰化不改变其生物活性,脱去N-端氨基的CCK_8类似物即Suc-CCK_7与母体CCK_8相比,其活性明显增加。在Boc-CCK_7中,Met被NIe取代活性可完全保留,Gly~(29)被D-Ala取代后仍保留相当的活性,但Gly~(29)被β-Ala取代后则失去胆囊收缩活性;在Met~(28)-Gly~(29)区域引入刚性的r-内酰胺环作为构象限制,也导致活性完全丧失。

Structural-activity Relationships of Cholecystokinln Octapeptide

Six cholecystokinin C-terminal octapeptide (CCK_8) analogues were prepared by liquid peptide synthesis. The ability of CCK_8 analogues to induce the contraction of isolated guinea pig gall bladder were tested. The results showed that the N-terminal acetylation of CCK_8 didn't affect its potency; The desamino analog of CCK_8 (SucCCK_7) displayed a significantly increased potency as compared to that of CCK_8. In Boc-CCK_7, both methionine residues can be replaced by isosteric norleucine without change of biological activity; Substitution of the Gly~(29) residue by a D-Ala led to a peptide whose potency was reduced but still behavied as agonist. In contrast, introduction of a β-Ala in position 29 of Boc-CCK_7 led to complete loss of activity. The incorporation of a synthesized γ-lactam bridged dipeptide (γ-Lac-Gly) as a conformational constraint into the peptide backbone resulted in a compound which was inactive in gall bladder bioassay.