New selective and potent 5-HT(1B/1D) antagonists: chemistry and pharmacological evaluation of N-piperazinylphenyl biphenylcarboxamides and biphenylsulfonamides.
New selective and potent 5-HT(1B/1D) antagonists: chemistry and pharmacological evaluation of N-piperazinylphenyl biphenylcarboxamides and biphenylsulfonamides.
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新型选择性强效 5-HT(1B/1D) 拮抗剂：N-哌嗪基苯基联苯甲酰胺和联苯磺酰胺的化学和药理学评价。
DOI：
10.1021/jm990397l
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发表时间：
2000
影响因子：
7.3
通讯作者：
Håkan V Wikström
中科院分区：
文献类型：
--
作者：
Yi Liao;H. Böttcher;Jürgen Harting;H. Greiner;C. van Amsterdam;T. Cremers;Staffan Sundell;Joachim März;Wilfried Rautenberg;Håkan V Wikström
合成了N-[4-甲氧基-3-（4-甲基哌嗪-1-基）苯基]-2 '-甲基-4'-（5-甲基-1，2，4-恶二唑-3-基）联苯-4-甲酰胺（1; GR 127935）的一系列新类似物，并对其进行了体外活性评价。它们的受体结合谱与1的受体结合谱相当。1，3，4-恶二唑异构体2和1的4 '-氨基羰基和4'-脒基类似物（9和10）对大鼠5-HT（1B）受体具有更高的亲和力（IC（50）= 0.93，1. 3和0.5 nM）和小牛5-HT（1D）受体（IC（50）分别为37、10和3 nM）的浓度高于1（大鼠5-HT（1B）和小牛5-HT（1D）受体分别为1.6和52 nM）。在5-HT（1B/1D）拮抗特性的功能性体外试验中，2、9、10、11 b（2的O-脱甲基衍生物）、13 a（2的O-甲磺酰基类似物）和16（与2不同，具有磺酰胺接头）在豚鼠皮质中K（+）诱导的5-HT释放中显示出比1和3更显著的作用（SB 224289）。化合物2、9和10在兔隐静脉模型中与1同样有效（pA（2）> 9）。在大鼠脑中进行的生物化学研究表明，2能够增强西酞普兰（一种选择性5-羟色胺再摄取抑制剂，SSRI）诱导的大鼠腹侧海马5-HT释放，同时防止西酞普兰给药引起的乙酰胆碱释放减少。通过单晶X射线衍射分析确定了2的分子结构。计算了这些化合物的log P和log D值。本研究有助于N-哌嗪基苯基联苯甲酰胺作为选择性和有效的5-HT（1B/1D）拮抗剂的SAR研究。
A series of new analogues of N-[4-methoxy-3-(4-methylpiperazin-1-yl)phenyl] 2'-methyl-4'-(5-methyl-1,2,4-oxadiazol-3-yl)biphenyl-4-carboxamide (1; GR127935) as potent and selective 5-HT(1B/1D) antagonists were synthesized and evaluated pharmacologically. Their receptor binding profiles were comparable to that of 1. The 1,3,4-oxadiazole isomer 2 and the 4'-aminocarbonyl and 4'-amidinyl analogues (9 and 10) of 1 had higher affinities at the rat 5-HT(1B) receptor (IC(50) = 0.93, 1. 3, and 0.5 nM, respectively) and calf 5-HT(1D) receptor (IC(50) = 37, 10, and 3 nM, respectively) than did 1 (1.6 and 52 nM for rat 5-HT(1B) and calf 5-HT(1D) receptors, respectively). In the functional in vitro testing of 5-HT(1B/1D) antagonistic properties, 2, 9, 10, 11b (O-demethylated derivative of 2), 13a (O-methylsulfonyl analogue of 2), and 16 (which differs from 2 with a sulfonamide linker) showed more pronounced effects in the K(+)-induced 5-HT release in the cortex of guinea pig than did 1 and 3 (SB224289). Compounds 2, 9, and 10 were equally potent as 1 in rabbit saphenous vein model (pA(2) > 9). A biochemical study of 2 with in vivo microdialysis in the rat brain showed that it is capable of augmenting citalopram (a selective serotonin reuptake inhibitor, SSRI) induced 5-HT release in rat ventral hippocampus, while preventing the decrease in acetylcholine release elicited by citalopram administration. The molecular structure of 2 was determined by single-crystal X-ray analysis. The log P and log D values of these compounds were calculated. This study contributes to the SAR study of N-piperazinylphenyl biphenylcarboxamides as selective and potent 5-HT(1B/1D) antagonists.