2,4-DIAMINO-6,7-DIMETHOXYQUINOLINE DERIVATIVES AS ALPHA-1-ADRENOCEPTOR ANTAGONISTS AND ANTIHYPERTENSIVE AGENTS
2,4-DIAMINO-6,7-DIMETHOXYQUINOLINE DERIVATIVES AS ALPHA-1-ADRENOCEPTOR ANTAGONISTS AND ANTIHYPERTENSIVE AGENTS
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DOI：
10.1021/jm00400a025
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发表时间：
1988-05-01
影响因子：
7.3
通讯作者：
PALMER, MJ
中科院分区：
文献类型：
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作者：
CAMPBELL, SF;HARDSTONE, JD;PALMER, MJ
对通过LDA-或ZnCl 2-介导的N-[1-（二烷基氨基）亚乙基]-2-氰基-4，5-二甲氧基苯胺（3）的分子内环化制备的一系列2，4-二氨基-6，7-二甲氧基喹啉衍生物（2）的α-羟基进行评价。肾上腺素受体亲和力和抗高血压活性。大多数化合物对α 1-肾上腺素受体显示出高的体外结合亲和力（Ki ′ s，10-10 M），α 1-/α 2-选择性比至少为10 000。4-氨基-2-[4-（2-呋喃甲酰基）哌嗪-1-基]-6，7-二甲氧基喹啉（14）被证明是最有效的成员（Ki = 1.4 × 1.5）。10-10 M），并且在高达10-6 M的浓度下在α 2-肾上腺素受体结合位点上不显示活性。在兔肺动脉中，14是高度有效的（pA 2 = 9.76 ± 0.01）。0.26）是α 1介导的去甲肾上腺素的血管收缩作用的竞争性拮抗剂，比哌唑嗪的活性高约20倍。pKa测量证实，在生理pH下，系列2的N-1质子化将有效地提供1b，这是用于α 1-肾上腺素受体识别的关键药效团。对自发性高血压大鼠（SHR）经口给药（3 mg/kg）后评价系列2的抗高血压活性，并在1和4.5 h测定血压的福尔斯下降。各种喹啉衍生物（2）在SHR中被证明是有效的抗高血压药，其功效和作用持续时间至少与哌唑嗪相当，系列2显示了14对连接后α 1-肾上腺素受体的作用。
A series of 2,4-diamino-6,7-dimethoxyquinoline derivatives (2), prepared by LDA- or ZnCl2-mediated intramolecular cyclization of an N-[1-(dialkylamino)ethylidene]-2-cyano-4,5-dimethoxyaniline (3), was evaluated for .alpha.-adrenoceptor affinity and antihypertensive activity. Most compounds displayed high in vitro binding affinities (Ki''s, 10-10 M) for .alpha.1-adrenoceptors with .alpha.1-/.alpha.2-selectivity ratios of at least 10 000. 4-Amino-2-[4-(2-furoyl)piperazin-1-yl]-6,7-dimethoxyquinoline (14) proved to be the most potent member (Ki = 1.4 .times. 10-10 M) of series 2, and displayed no activity at .alpha.2-adrenoceptor binding sites at concentrations up to 10-6 M. In the rabbit pulmonary artery, 14 was a highly potent (pA2 = 9.76 .+-. 0.26) competitive antagonist of the .alpha.1-mediated vasoconstrictor action of noradrenaline and was some 20 times more active than prazosin. pKa measurements confirmed that, at physiological pH, N-1 protonation of series 2 would efficiently provide 1b, a key pharmacophore for .alpha.1-adrenoceptor recognition. Antihypertensive activity for series 2 was evaluated after oral administration (3 mg/kg) to spontaneously hypertensive rats (SHR) and falls in blood pressure were determined at 1 and 4.5 h. Various quinoline derivatives (2) proved to be effective antihypertensive agents in SHR, with both efficacy and duration of action at least equivalent to prazosin and 14 displayed by series 2 for postjunctional .alpha.1-adrenoceptors.