Design and synthesis of highly selective in vitro and in vivo uterine receptor antagonists of oxytocin: comparisons with Atosiban.
Design and synthesis of highly selective in vitro and in vivo uterine receptor antagonists of oxytocin: comparisons with Atosiban.
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催产素的高选择性体外和体内子宫受体拮抗剂的设计和合成：与阿托西班的比较。
DOI：
10.1111/j.1399-3011.1995.tb00596.x
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发表时间：
1995
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;Miteva,K;Pancheva,S;Stoev,S;Wo,NC;Chan,WY
我们报道了我们的一个先导催产素拮抗剂的七个二位类似物(多肽1-7)的固相合成和一些药理性质。DES-9-甘氨酰胺[1-(β-Mercapto-β，β-五亚甲基丙酸)，2-O-甲基酪氨酸，4-苏氨酸]鸟氨酸(Des-Gly-NH2，d(CH2)5-[Tyr(Me)2，Thr4]OVT)(A)。肽1-7在第二位具有以下取代基：(1)d-Tyr(Me)；(2)L-Tyr(ET)；(3)d-Tyr(ET)；(4)L-Tyr；(5)d-Tyr；(6)d-Phe和(7)d-Trp。在体外和体外OT法、活体加压药(V1a-受体)和体内抗利尿剂(V2-受体)试验中对这些化合物的激动剂和拮抗剂活性进行了评估。这七种多肽都没有催产素或加压素激动剂。多肽1、2、4、6和7是极弱的V2激动剂(V2活性在0.001~0.02U/mg之间)。多肽3和5具有较弱的V2拮抗作用(PA2>；6.0和>；5.5)。多肽1-7在体外表现出潜在的(无镁离子)OT拮抗作用(抗OT pA2值在7.66~8.03之间)。多肽1和4-7显示出潜在的活体OT拮抗作用。体内估计的抗OT pA2值在7.06到7.79之间(多肽2和3没有被测试)。当抗VapA2的值在5.17-6.25之间时，所有7个多肽的抗V1a活性均低于亲本多肽(A)(抗V1a)。PA2=6.46)。其中4个多肽(4-7)在体外和体内抗OT/抗V1a方面均有显著提高。THED-Tyr2(5)、d-Trp2(7)、d-Phe2(6)和1-Tyr2(4)类似物(A)的体外选择性/抗V1选择性分别为240、390、404和540。L-Tyr2(4)、d-Trp2(7)、d-Phe2(6)和d-Tyr2(5)类似物的体内抗OT/抗V1选择性分别为72、80、88和95。多肽4-7似乎是迄今为止报道的最具选择性的多肽OT拮抗剂。在这方面，可以注意到，它们似乎与密切相关的OT拮抗剂1-脱氨基[D-Tyr(ET)2，Thr1]OVT(Atosiban)一样有效或更具选择性，后者目前正在进行临床试验，作为预防早产的潜在治疗剂。Atosiban(肽8)在我们的实验室进行了重新合成和药理评价。阿托西班表现出以下对抗能力。抗OT(体外，无镁)PA2=7.71，抗Otin vivopA2=7.05，抗V1pA2=6.14，抗V2pA2≅5.9。其体内抗OT/抗V1asA的选择性为8。其中一些拮抗剂可能是用于治疗早产的潜在解宫剂。它们也可以作为研究催产素生理作用的有用的新药理学工具。最后，本文的发现为设计更有效、更有选择性的OT拮抗剂提供了有用的线索。
We report the solid phase synthesis and some pharmacological properties of seven position two analogues (peptides 1–7) of one of our lead oxytocin antagonists. des‐9‐glycinamide[1‐(β‐mercapto‐β, β‐pentamethylenepropionic acid), 2‐O‐methyltyrosine, 4‐threonine]ornithinevasotocin(desGly‐NH2,d(CH2)5‐ [Tyr(Me)2,Thr4]OVT) (A). Peptides 1–7 have the following substituents at position two (1)d‐Tyr(Me); (2)l‐Tyr(Et); (3)d‐Tyr(Et); (4)l‐Tyr; (5)d‐Tyr; (6)d‐Phe and (7)d‐Trp. These were evaluated for agonistic and antagonistic activities inin vitroandin vitroOT assays,in vivovasopressor (V1a‐receptor) assays andin vivoantidiuretic (V2‐receptor) assays. None of the seven peptides exhibits oxytocic or vasopressor agonism. Peptides 1,2,4,6 and 7 are extremely weak V2agonists (V2activities range from 0.001 to 0.02 U/mg). Peptides 3 and 5 exhibit weak V2antagonism (pA2>6.0 and >5.5, respectively). Peptides 1–7 exhibit potentin vitro(no Mg2+) OT antagonism (anti‐OT pA2values range from 7.66 to 8.03). Peptides 1 and 4–7 exhibit potentin vivoOT antagonism. Estimated in vivo anti‐OT pA2values range from 7.06 to 7.79 (peptides 2 and 3 were not tested). With anti‐VlapA2values of 5.17‐6.25 all seven peptides exhibit reduced anti‐V1a, potencies relative to the parent peptide (A) (anti‐V1a. pA2= 6.46). Four of these peptides (4‐7) exhibit striking gains inin vitroandin vivoanti‐OT/anti‐V1a. selectivities compared to (A) which has anin vitroselectivity of 30 and anin vivoselectivity of 18. Thed‐Tyr2(5),d‐Trp2(7),d‐Phe2(6) andl‐Tyr2(4) analogues of (A) exhibit anti‐OT (in vitro)/anti‐V1aselectivities = 240, 390, 404 and 540, respectively. Thel‐Tyr2(4),d‐Trp2(7),d‐Phe2(6)andd‐Tyr2(5) analogues exhibited anti‐OT (in vivo)/anti‐V1aselectivities of 72, 80, 88 and 95, respectively. Peptides 4–7 appear to be the most selective peptide OT antagonists reported to date. In this regard it may be noted that they appear to be as or more potent and much more selective than the closely related OT antagonist 1‐deamino[D‐Tyr(Et)2,Thr1]OVT (Atosiban) which is currently undergoing clinical trial as a potential therapeutic agent for the prevention of premature labor. Atosiban (peptide 8) was resynthesized and pharmacologically evaluated in our laboratories. Atosiban exhibits the following antagonistic potencies. Anti‐OT (in vitro, no Mg2) pA2= 7.71; anti‐OTin vivopA2= 7.05; anti‐V1pA2= 6.14 and anti‐V2pA2≅ 5.9. Its anti‐OT (in vivo)/anti‐V1aselectivity is 8. Some of these antagonists may be suitable candidates for evaluation as potential tocolytic agents for use in the treatment of pre‐term labor. They could also serve as useful new pharmacological tools for studies on the physiological roles of oxytocin. Finally, the findings presented here provide useful clues for the design of more potent and more selective OT antagonists.
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1-L-青霉胺催产素、1-D-青霉胺催产素和 1-脱氨基青霉胺催产素的合成，是催产素催产反应的有效抑制剂。
影响因子：
7.3
作者：
H. Schulz;V. du Vigneaud
通讯作者：
V. du Vigneaud
铯盐全星化制备Merrifield树脂
DOI：
--
发表时间：
1973
期刊：
影响因子：
--
作者：
B. Gisin
通讯作者：
B. Gisin
长效催产素拮抗剂的设计：用于治疗早产的潜在保胎剂。
DOI：
--
发表时间：
1986
期刊：
The Journal of pharmacology and experimental therapeutics
影响因子：
--
作者：
Chan,WY;Hruby,VJ;Rockway,TW;Hlavacek,J
通讯作者：
Hlavacek,J
DOI：
10.1111/j.1399-3011.1980.tb02962.x
发表时间：
2009-01
期刊：
International journal of peptide and protein research
影响因子：
--
作者：
K. Bańkowski;M. Manning;J. Seto;J. Haldar;Wilbur H. Sawyer
通讯作者：
K. Bańkowski;M. Manning;J. Seto;J. Haldar;Wilbur H. Sawyer
加压素和催产素的受体特异性拮抗剂
DOI：
--
发表时间：
1993
期刊：
影响因子：
--
作者：
Maurice Manning;S. Stoev;W. Y. Chan;Wilbur H. Sawyer
通讯作者：
Wilbur H. Sawyer