2-[(4-phenylpiperazin-1-yl)methyl]imidazo(di)azines as selective D4-ligands.: Induction of penile erection by 2-[4-(2-methoxyphenyl)piperazin-1-ylmethyl]imidazo[1,2-a]pyridine (PIP3EA), a potent and selective D4 partial agonist
2-[(4-phenylpiperazin-1-yl)methyl]imidazo(di)azines as selective D4-ligands.: Induction of penile erection by 2-[4-(2-methoxyphenyl)piperazin-1-ylmethyl]imidazo[1,2-a]pyridine (PIP3EA), a potent and selective D4 partial agonist
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DOI：
10.1021/jm060166w
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发表时间：
2006-06-29
影响因子：
7.3
通讯作者：
Gueiffier, Alain
中科院分区：
文献类型：
--
作者：
Enguehard-Gueiffier, Cecile;Huebner, Harald;Gueiffier, Alain
制备了一系列新型 2-[(4-苯基哌嗪-1-基)甲基]咪唑嗪和氮杂类似物，并针对选定的多巴胺、血清素和肾上腺素能受体亚型进行了筛选。 2-取代的咪唑并吡啶和哒嗪对D-4多巴胺受体具有高亲和力和选择性。虽然功能实验表明大多数目标化合物具有中性拮抗剂或微弱的部分激动剂作用，但 2-甲氧基苯基取代的 2-哌嗪基甲基咪唑吡啶 3c (PIP3EA) 在有丝分裂实验和 GTP gamma S 结合测试中显示出显着的激动剂功效，EC50 值分别为 3.0 (46%) 和 4.5 nM (57%)。当给予大鼠时，我们的 D-4 激动剂 3c 可诱导体内阴茎勃起。这种效应被 D-4 选择性拮抗剂 L-745,870 抑制，证实了这一机制途径。
A series of novel 2-[( 4-phenylpiperazin-1-yl) methyl] imidazoazines and aza-analogues were prepared and screened at selected dopamine, serotonin, and adrenergic receptor subtypes. 2- Substituted imidazopyridines and pyridazines presented high affinities and selectivities for D-4 dopamine receptors. Whereas functional experiments indicated neutral antagonists or weak partial agonist effects for most of the target compounds, the 2- methoxyphenyl substituted 2-piperazinylmethylimidazopyridine 3c ( PIP3EA) displayed substantial agonist efficacy in mitogenesis experiments and GTP gamma S binding tests, resulting in EC50 values of 3.0 ( 46%) and 4.5 nM ( 57%), respectively. Our D-4 agonist 3c induced penile erection in vivo when administered to rats. This effect was inhibited by L-745,870 a D-4 selective antagonist, confirming the mechanistic pathway.