5-HT1B receptor antagonist properties of novel arylpiperazide derivatives of 1-naphthylpiperazine.
5-HT1B receptor antagonist properties of novel arylpiperazide derivatives of 1-naphthylpiperazine.
复制标题
1-萘基哌嗪新型芳基哌嗪衍生物的 5-HT1B 受体拮抗剂特性。
DOI：
10.1021/jm9703552
复制
发表时间：
1997
影响因子：
7.3
通讯作者：
S. Halazy
中科院分区：
文献类型：
--
作者：
C. Jorand;P. Pauwels;C. Palmier;C. Moret;P. Chopin;M. Pérez;M. Marien;S. Halazy
制备了一系列新的通式4的1-萘基哌嗪的芳基哌嗪衍生物，并将其评价为5-HT 1B拮抗剂。在克隆的人5-HT 1A、5-HT 1B和5-HT 1D受体上的结合实验表明，这些衍生物是5-HT 1B/1D亚型的有效和选择性配体，与1-萘基哌嗪（1-NP）相比，对5-HT 1A受体的结合选择性增加。抑制由人5-HT 1B受体介导的毛喉素刺激的cAMP形成的研究表明，芳基哌嗪取代基的性质调节这些1-NP衍生物的固有活性。其中，2-[[8-（4-甲基哌嗪-1-基）萘-2-基]氧基] -1-（4-邻甲苯基哌嗪-1-基）乙酮（4a）被鉴定为有效的中性5-HT 1B拮抗剂，能拮抗5-CT（5-氨基甲酰基色胺）对豚鼠下丘脑脑片5-HT释放的抑制。此外，发现4a在口服给药后在豚鼠体内有效地拮抗由选择性5-HT 1B/1D激动剂诱导的体温降低（ED 50 = 0.13 mg/kg）。
A new series of arylpiperazide derivatives of 1-naphthylpiperazine of general formula 4 has been prepared and evaluated as 5-HT1B antagonists. Binding experiments at cloned human 5-HT1A, 5-HT1B, and 5-HT1D receptors show that these derivatives are potent and selective ligands for 5-HT1B/1D subtypes with increased binding selectivity versus the 5-HT1A receptor when compared to 1-naphthylpiperazine (1-NP). Studies of inhibition of the forskolin-stimulated cAMP formation mediated by the human 5-HT1B receptor demonstrate that the nature of the arylpiperazide substituent modulates the intrinsic activity of these 1-NP derivatives. Among them, 2-[[8-(4-methylpiperazin-1-yl)naphthalen-2-yl]oxy] -1-(4-o-tolylpiperazin-1-yl)ethanone (4a) was identified as a potent neutral 5-HT1B antagonist able to antagonize the inhibition of 5-HT release induced by 5-CT (5-carbamoyltryptamine) in guinea pig hypothalamus slices. Moreover, 4a was found to potently antagonize the hypothermia induced by a selective 5-HT1B/1D agonist in vivo in the guinea pig following oral administration (ED50 = 0.13 mg/kg).