In vitro studies on L-771,688 (SNAP 6383), a new potent and selective α1A-adrenoceptor antagonist
In vitro studies on L-771,688 (SNAP 6383), a new potent and selective α1A-adrenoceptor antagonist
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DOI：
10.1016/s0014-2999(00)00854-2
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发表时间：
2000-12-15
影响因子：
5
通讯作者：
Forray, C
中科院分区：
文献类型：
--
作者：
Chang, RSL;Chen, TB;Forray, C
L-771，688（SNAP 6383，甲基（4S）-4-（3，4-二氟苯基）-6-[（甲氧基）甲基]-2-氧代-3-[（{3-[4-（2-吡啶基）-1-哌啶基]丙基）氨基）羰基]-1，2，3，4-四氢-5-嘧啶甲酸酯）具有高亲和力（Ki小于或等于1 nM），对[H-3]哌唑嗪与克隆的人、大鼠和犬α（1A）-肾上腺素受体的结合具有高选择性（> 500倍），超过α（1B）和α（1D）-肾上腺素受体。在已知含有α（1A）和非α（1A）-肾上腺素受体的人体和动物组织中进行的[H-3]哌唑嗪/（+/-）-β [I-125]-4-羟基-苯基）-乙基-氨甲基-特拉酮（[I-125]HEAT）结合研究进一步证明了L-771，688的效价和α（1A）-亚型选择性。[H-3]L-771，688在克隆的人α（1A）-肾上腺素受体和大鼠组织中的结合研究表明，特异性[H-3]L-771，688结合是可饱和的，具有高亲和力（Kd = 43-90 pM），并代表了与α（1A）-肾上腺素受体的结合。L-771，688拮抗去甲肾上腺素诱导的克隆人α（1A）-肾上腺素受体磷酸肌醇反应，以及苯肾上腺素或A-61603（N-[5- 4，5-二氢-1H-咪唑-2基）-2-羟基-5，6，7，8-四氢-萘-1-基]甲磺酰胺氢溴酸盐）在分离的大鼠、狗和人前列腺中诱导收缩，人和猴膀胱颈和大鼠尾动脉，表观K-b值为0.02-0.28 nM。相反，去甲肾上腺素引起的大鼠主动脉收缩对L-771，688有抵抗作用。这些数据表明，L-771，688是一种高度选择性的α（1A）-肾上腺素受体拮抗剂。(C)2000 Elsevier Science B. V.保留所有权利。
L-771,688 (SNAP 6383, methyl(4S)-4-(3,4-difluorophenyl)-6-[(methyloxy)methyl]-2-oxo-3-[({3-[4-(2-pyridinyl)-1- piperidinyl]propyl)amino)carbonyl]-1,2,3,4-tetrahydro-5-pyrimidinecarboxylate) had high affinity(K-i less than or equal to 1 nM) for [H-3]prazosin binding to cloned human, rat and dog alpha (1A)-adrenoceptors and high selectivity (> 500-fold) over alpha (1B) and alpha (1D)-adrenoceptors. [H-3]Prazosin/(+/-)-beta[I-125]-4-hydroxy-phenyl)-ethyl-aminomethyl-teralone([I-125]HEAT) binding studies in human and animal tissues known to contain alpha (1A) and non-alpha (1A)-adrenoceptors further demonstrated the potency and alpha (1A)-subtype selectivity of L-771,688. [H-3]L-771,688 binding studies at the cloned human alpha (1A)-adrenoceptors and in rat tissues indicated that specific [H-3]L-771,688 binding was saturable and of high affinity(K-d = 43-90 pM) and represented binding to the pharmacologically relevant alpha (1A)-adrenoceptors. L-771,688 antagonized norepinephrine-induced inositol-phosphate responses in cloned human alpha (1A)-adrenoceptors, as well as phenylephrine or A-61603 (N-[5-4,5-dihydro-1H-imidazol-2yl)-2-hydroxy-5,6,7,8-terahydro-naphthlen-1-yl] methanesulfonamide hydrobromide) induced contraction in isolated rat, dog and human prostate, human and monkey bladder neck and rat caudal artery with apparent K-b values of 0.02-0.28 nM. In contrast, the contraction of rat aorta induced by norepinephrine was resistant to L-771,688. These data indicate that L-771,688 is a highly selective alpha (1A)-adrenoceptor antagonist. (C) 2000 Elsevier Science B.V. All rights reserved.