Charpentier B, Dor A, Roy P, England P, Pham H, Durieux C, Roques B P
U 266 INSERM, UA 498 CNRS, U.E.R. des Sciences Pharmaceutiques et Biologiques, Paris, France.
J Med Chem. 1989 Jun;32(6):1184-90. doi: 10.1021/jm00126a007.
To investigate the role of the sulfate group and the influence of cyclization on the biological properties of conformationally constrained CCK8 analogues, three series of compounds were synthesized: Boc-Glu-Tyr-Nle-D-Lys-Trp-Nle-Asp-Phe-NH2 (1), Boc-Glu-Tyr(SO3H)-Nle-D-Lys-Trp-Nle-Asp-Phe-NH2 (2), and Boc-Glu-Tyr-(SO3H)-Nle-D-Lys-Trp-Nle-Asp-Phe-NH2 (3) (series A); Boc-D-Glu-Tyr-Nle-D-Lys-Trp-Nle-Asp-Phe-NH2 (4), Boc-D-Glu-Tyr(SO3H)-Nle-D-Lys-Trp-Nle-Asp-Phe-NH2 (5), Boc-D-Glu-Tyr(SO3H)-Nle-D-Lys-Trp-Nle-Asp-Phe-NH2 (6), and Boc-D-Glu-Tyr(SO3H)-Nle-D-Nle-Trp-Asp-Phe-NH2 (7) (series B); and Boc-gamma-D-Glu-Tyr-Nle-D-Lys-Trp-Nle-Asp-Phe-NH2 (8), Boc-gamma-D-Glu-Tyr(SO3H)-Nle-D-Lys-Trp-Nle-Asp-Phe-NH2 (9), and Boc-gamma-D-Glu-Tyr-(SO3H)-Nle-D-Lys-Trp-Nle-Asp-Phe-NH2 (10) (series C). The selectivity of these peptides was studied by measuring their ability to displace [3H]propionyl-CCK8 from guinea pig brain and pancreatic membranes. All the peptides displayed low affinities (KI values around 10(-6) M) for the pancreatic receptors (A type). In contrast, both sulfated and nonsulfated cyclic analogues displayed high affinities for central-type binding sites (B type), especially compounds belonging to series C [KI(8) = 4.7 nM and KI(9) = 0.56 nM]. In all series the linear analogues had relatively poor affinities (KI approximately 300 nM) for B-type receptors. Compound 9 was the most potent (KI = 0.56 nM) and selective [KI(pancreas)/KI(brain) = 4464] for central-type CCK receptors of guinea pig. The cyclization of the N-terminal region of CCK8 permits one therefore to obtain probes for central receptors, and small changes directed toward the cyclic part modulate the affinity for these receptors.
为了研究硫酸根基团的作用以及环化对构象受限的胆囊收缩素八肽（CCK8）类似物生物学特性的影响，合成了三个系列的化合物：Boc-Glu-Tyr-Nle-D-Lys-Trp-Nle-Asp-Phe-NH2（1）、Boc-Glu-Tyr(SO3H)-Nle-D-Lys-Trp-Nle-Asp-Phe-NH2（2）和Boc-Glu-Tyr-(SO3H)-Nle-D-Lys-Trp-Nle-Asp-Phe-NH2（3）（A系列）；Boc-D-Glu-Tyr-Nle-D-Lys-Trp-Nle-Asp-Phe-NH2（4）、Boc-D-Glu-Tyr(SO3H)-Nle-D-Lys-Trp-Nle-Asp-Phe-NH2（5）、Boc-D-Glu-Tyr(SO3H)-Nle-D-Lys-Trp-Nle-Asp-Phe-NH2（6）和Boc-D-Glu-Tyr(SO3H)-Nle-D-Nle-Trp-Asp-Phe-NH2（7）（B系列）；以及Boc-γ-D-Glu-Tyr-Nle-D-Lys-Trp-Nle-Asp-Phe-NH2（8）、Boc-γ-D-Glu-Tyr(SO3H)-Nle-D-Lys-Trp-Nle-Asp-Phe-NH2（9）和Boc-γ-D-Glu-Tyr-(SO3H)-Nle-D-Lys-Trp-Nle-Asp-Phe-NH2（10）（C系列）。通过测量这些肽从豚鼠脑和胰腺膜中置换[3H]丙酰基-CCK8的能力，研究了它们的选择性。所有肽对胰腺受体（A型）显示出低亲和力（KI值约为10(-6) M）。相比之下，硫酸化和非硫酸化的环状类似物对中枢型结合位点（B型）显示出高亲和力，尤其是属于C系列的化合物[KI(8) = 4.7 nM和KI(9) = 0.56 nM]。在所有系列中，线性类似物对B型受体的亲和力相对较差（KI约为300 nM）。化合物9对豚鼠中枢型CCK受体最有效（KI = 0.56 nM）且具有选择性[KI(胰腺)/KI(脑) = 4464]。因此，CCK8 N端区域的环化使得能够获得针对中枢受体的探针，并且针对环状部分的微小变化会调节对这些受体的亲和力。
