Iskra-Jopa Joanna, Gołembiowska Krystyna, Dziubina Anna, Cybulski Marcin, Duszyńska Beata, Chilmonczyk Zdzisław
Pharmaceutical Research Institute, Rydygiera 8, PL-01-793 Warszawa, Poland.
J Pharm Pharmacol. 2005 Feb;57(2):205-11. doi: 10.1211/0022357055425.
Two 1,2,4-substituted derivatives of piperazine were tested for their effect on dopamine and serotonin (5-HT) release in rat prefrontal cortex. Both compounds, 1-[4-(4-chinolin-2-yl-piperazin-1yl)-butyl]piperidin-2-on (MM5) and 1-[4-(2-methyl-4-chinolin-2-yl-piperazin-1-yl)-butyl]-8-azaspiro [4.5]decano-7,9-dion (MC1), produced hypothermia in mice and showed affinity for 5-HT1A receptors in-vitro. Like the selective 5-HT1A agonist 8-OH-DPAT (0.1 mg kg(-1)), MM5 given peripherally (30 mg kg(-1)) decreased the extracellular 5-HT level in rat prefrontal cortex, while MC1 suppressed 5-HT release at a higher dose (40 mg kg(-1)), but not at a lower one (30 mg kg(-1)). The effect of both compounds on 5-HT release was abolished by WAY 100635 (0.3 mg kg(-1)). MC1 (30 and 40 mg kg(-1)), but not MM5, raised cortical dopamine, 3,4-dihydroxyphenylacetic acid (DOPAC) and extracellular homovanillic acid (HVA) levels. The effect of MC1 on dopamine release was reversed by neither WAY 100635 nor the non-selective 5-HT2 antagonist ritanserin (2 mg kg(-1)). However, ritanserin prevented the effect of the higher dose of MC1 on 5-HT release. The results of this study suggest that MM5 exhibits the profile of a 5-HT1A agonist devoid of dopaminergic activity. MC1 seems to possess moderate agonist activity at 5-HT1A and 5-HT2A receptors, while acting on 5-HT release in the rat prefrontal cortex. However, the facilitation of dopamine release by this compound does not seem to be related to its affinity for 5-HT1A and 5-HT2A receptors.
对两种1,2,4-取代的哌嗪衍生物进行了测试，以研究它们对大鼠前额叶皮质中多巴胺和5-羟色胺（5-HT）释放的影响。这两种化合物，即1-[4-(4-喹啉-2-基-哌嗪-1-基)-丁基]哌啶-2-酮（MM5）和1-[4-(2-甲基-4-喹啉-2-基-哌嗪-1-基)-丁基]-8-氮杂螺[4.5]癸烷-7,9-二酮（MC1），可使小鼠体温降低，并在体外显示出对5-HT1A受体的亲和力。与选择性5-HT1A激动剂8-羟基二丙胺基四氢萘（8-OH-DPAT，0.1 mg kg(-1)）一样，外周给予MM5（30 mg kg(-1)）可降低大鼠前额叶皮质细胞外5-HT水平，而MC1在较高剂量（40 mg kg(-1)）时可抑制5-HT释放，但在较低剂量（30 mg kg(-1)）时则无此作用。WAY 100635（0.3 mg kg(-1)）可消除这两种化合物对5-HT释放的影响。MC1（30和40 mg kg(-1)）可提高皮质多巴胺、3,4-二羟基苯乙酸（DOPAC）和细胞外高香草酸（HVA）水平，但MM5无此作用。MC1对多巴胺释放的影响既不能被WAY 100635逆转，也不能被非选择性5-HT2拮抗剂利坦色林（2 mg kg(-1)）逆转。然而，利坦色林可阻止较高剂量的MC1对5-HT释放的影响。本研究结果表明，MM5表现出一种无多巴胺能活性的5-HT1A激动剂的特征。MC1似乎在5-HT1A和5-HT2A受体上具有适度的激动剂活性，同时作用于大鼠前额叶皮质中的5-HT释放。然而，该化合物对多巴胺释放的促进作用似乎与其对5-HT1A和5-HT2A受体的亲和力无关。
