Novel approach to the design of synthetic radioiodinated linear V1A receptor antagonists of vasopressin.
Novel approach to the design of synthetic radioiodinated linear V1A receptor antagonists of vasopressin.
复制标题
设计合成放射性碘标记的加压素线性 V1A 受体拮抗剂的新方法。
DOI：
10.1111/j.1399-3011.1992.tb00300.x
复制
发表时间：
1992
期刊：
影响因子：
--
通讯作者：
Chan,WY
中科院分区：
文献类型：
--
作者：
Manning,M;Bankowski,K;Barberis,C;Jard,S;Elands,J;Chan,WY
我们报道了六种有效的选择性线性AVP血管加压剂（v1受体）拮抗剂的固相合成：Phaa1‐d‐Tyr(Et)2‐Phe3‐Gln4‐Asn5‐Lys6‐Pro7‐Arg‐NH28(A) （Phaa =苯乙酰基），其中Phaa1残基被羟基苯基乙酰基（HO‐Phaa）、羟基苯基丙酰（HO‐Phpa）和苯丙酰（Phpa）取代，而Tyr(Et)2和Lys6残基byd‐Tyr(Me)2和arg6取代基取代。合成了含酚肽，以测试使用该方法设计AVP v1受体高亲和力选择性配体的可行性。合成了A的下列类似物：[(HO) Phaa1];2. [(HOPhpa1 d检测酪氨酸(我)2];3. [(HO) Phaa1 d检测酪氨酸(我)2、Arg6);4. [(HO) Phaa1 Arg6];5. [Phpa1];6. [(HO) Phpa1]。在大鼠血管加压（V1a受体）、抗利尿（V2受体）和体外促孕试验中检测了所有六种肽的激动和拮抗作用。还测定了含酚肽对肝v1和子宫受体的亲和力。含酚肽均表现出有效的v1拮抗剂。抗v1apa2值为8.23 ~ 8.63 （A的抗v1apa2值为8.69）。它们的抑制常数（Ki (nm)）在0.4 ~ 1.0之间。它们是弱抗利尿激动剂，活性范围为0.022 U/mg至0.13 U/mg （A = 0.033 U/mg）。它们在体外均表现出OT拮抗作用。抗OT pa2值范围为7.28 ~ 7.71 （A = 7.62）。所有五种酚类化合物都用氯化碘碘化，并在相同的体内和体外测定系统中进行检测。碘化衍生物均表现出较强的抗v11和抗OT作用。当肝脏中的Ki值为0.1 nM时，肽3和6的碘化衍生物的亲和力尤其令人印象深刻。这两种多肽作为Vla受体的潜在高亲和力、选择性配体，是非常有前途的放射性碘候选体。因此，该方法补充了利用酪氨酸取代的传统方法，为AVP v1受体、AVP垂体（V1b）受体、AVP v2受体和OT子宫受体的高亲和力放射配体的设计提供了希望。该方法也可用于其它生物活性肽的放射性配体的设计。
We report the solid phase synthesis of six analogs of the potent and selective linear AVP vasopressor (V1areceptor)antagonist: Phaa1‐d‐Tyr(Et)2‐Phe3‐Gln4‐Asn5‐Lys6‐Pro7‐Arg‐NH28(A) (where Phaa = phenylacetyl) in which the Phaa1residue is replaced by hydroxyphenylacetyl (HO‐Phaa), hydroxyphenylpropionyl (HO‐Phpa) and phenylpropionyl (Phpa) and thed‐Tyr(Et)2and Lys6residues byd‐Tyr(Me)2and Arg6substituents. The phenolic‐containing peptides were synthesized to test the feasibility of using this approach for the design of high affinity selective ligands for AVP V1areceptors. The following analogs of A were synthesized: 1. [(HO)Phaa1]; 2. [(HOPhpa1,d‐Tyr(Me)2]; 3. [(HO)Phaa1,d‐Tyr(Me)2,Arg6]; 4. [(HO)Phaa1,Arg6]; 5. [Phpa1]; 6. [(HO)Phpa1]. All six peptides were examined for agonistic and antagonistic potencies in vasopressor (V1a‐receptor) and antidiuretic (V2‐receptor) andin vitrooxytocic assays in rats. The affinities of the phenolic‐containing peptides for hepatic V1aand uterine receptors were also determined. The phenolic‐containing peptides all exhibit potent V1aantagonism. Their anti‐V1apA2values range from 8.23 to 8.63 (the anti‐V1apA2value of A = 8.69). Their inhibition constants (Ki in nm) range from 0.4 to 1.0. They are weak antidiuretic agonists with activities ranging from 0.022 U/mg to 0.13 U/mg (A = 0.033 U/mg). They all exhibit OT antagonismin vitro. Their anti‐OT pA2values range from 7.28 to 7.71 (A = 7.62). All five phenolic compounds were iodinated using iodine chloride and tested in the samein vivoandin vitroassay systems. The iodinated derivatives all exhibited potent V1aantagonism and OT antagonism. With Ki values in the liver of 0.1 nM the affinities of the iodinated derivatives of peptides 3 and 6 are particularly impressive. These two peptides are very promising candidates for radioiodination as potential high affinity, selective ligands for Vla receptors. Thus this approach which complements the traditional approach of utilizing tyrosine substitutions, offers promise for the design of high affinity radioligands for AVP V1areceptors, AVP pituitary (V1b) receptors, AVP V2receptors and OT uterine receptors. It may also have application for the design of radioligands for other biologically active peptides.